Clinical Aspects of Liver Diseases 29 Drug-induced liver damage

29 Drug-induced liver damage

Page:

1 Drugs as foreign substances 542

2 Frequency 542

3 Pathogenesis 543

3.1 Obligate hepatotoxins 543

3.2 Facultative hepatotoxins 544

4 Morphological reactions 544

4.1 Adaptive changes 544

4.2 Morphological changes 545

4.2.1 Steatosis 545

4.2.2 Necrosis 545

4.2.3 Cholestasis 546

4.2.4 Inflammatory reactions 547

4.2.5 Vascular reactions 548

4.2.6 Liver tumours 548

4.2.7 Fulminant liver failure 550

5 Clinical aspects 551

5.1 Clinical courses 551

5.2 Anamnesis 551

5.3 Clinical findings 552

5.4 Laboratory findings 552

5.5 Search for causes 552

5.6 Herbal remedies 553

5.7 Test procedures 554

5.7.1 Withdrawal trial 554

5.7.2 Re-exposure trial 554

6 Prognosis 554

7 Therapy 554

8 Hepatotoxic remedies (selection) 555

앫 References (1⫺134) 560

(Figures 29.1 ⫺29.15; tables 29.1⫺29.10)

1 Drugs as foreign substances

Xenobiotics: Xenobiotics are defined as exogenously administered or endogenously produced foreign sub- stances that impair and ultimately damage the ecol- ogy and homoeostasis of cellular systems. This defin- ition also includes medicinal preparations. (s. p. 52) All orally or parenterally administered drugs enter the liver and from here, after passing through biotransfor- mation systems, are released into the cardiovascular sys- tem in an unconverted or a metabolically converted state. In addition, systemic effects have to be anticipated in cases of topical administration (cutaneous, inhalant).

• Metabolic processes generate metabolites, more speci- fically catabolites ( ⫽ degradation products) and anabo- lites ( ⫽ synthesis products). These biochemical pro- cesses are catalyzed or controlled inside and outside the cell by enzymes, hormones and the neurovegetative sys- tem. • Exogenous substances may also be metabolized and excreted without enzymatic processing by spontan- eous chemical conversion ( ⫽ metabonates).

䉴 Of the many different xenobiotics, only a small fraction are sufficiently water-soluble to be excreted in an unchanged state via the kidneys or the bile. These are strongly polar groups such as penicillin, cephalosporin, tetracycline, thiazide, amiloride and cromoglycic acid; so far, no metabolites of these substances have been found. The phase-I reaction comprises non-synthetic pro- cesses such as the oxidation, reduction or hydrolysis of medicinal products. This largely takes place in the endoplasmic reticulum via the cytochrome P-450 isoenzyme system. For the metabolism of foreign substances, CYP 3 A 4 is quantitatively important.

•

bio- transformation, i.e. by the metabolic production of water-soluble

•

hepatic RES. (s. pp 64

•

non-variable factors such as genetics, gender and age, or by variable factors. In

3.18) (s. fig. 3.11)

•

Genetic polymorphism prevails if a certain enzyme variant is found

Medicaments that have a hepatic clearance of > 60% when passing through the liver (bioavailability ⫽ 30⫺40%) are termed “high clearance substances”. This rate of clearance depends on the hepatic circulation.

•

of < 30% (bioavailability⫽ 70⫺80%) are termed “low clearance substances”. The clearance process itself largely depends on the metabolic function of the liver.

•

The recognition that a system which metabolizes drug products can also produce highly reactive toxic meta- bolites has proved crucial. As the liver has the highest number of enzyme biotransformation systems, it is the main site of production of such reactive metabolites and is thus more susceptible to damage. • Medicaments must therefore be regarded as potentially hepatotoxic sub- stances. Basically, they can trigger a vast range of func- tional and morphological changes in the liver. The resulting hepatic damage can mimic almost any acute or chronic liver disease. This means that in terms of func- tion, morphology and clinical presentation, it is virtually impossible to differentiate between drug-induced liver dis- eases and the non-iatrogenic liver diseases they mimic.

Drugs always have to be considered in the differential diagnosis of any case of liver disease lacking un- equivocal clarification. The diagnosis of a pharma- con-related liver disease depends on the reliable exclusion of other potential causes of the existing dis- ease as well as on the so-called withdrawal trial.

2 Frequency

Quantification: With regard to their frequency, adverse side effects are classified as (1.) frequent (>10%), (2.) occasional (1 ⫺10%), (3.) rare (<1%), (4.) very rare (<0.1%), and (5.) isolated cases (not yet quantifiable).

Surprisingly ⫺ but also understandably, given the great

difficulties related to any reliable quantification ⫺ very

little information is available regarding the frequency of

adverse side effects in patients taking medication. A

total of 2.3% or 1.9 ⫺6.2%, sometimes even up to 20%,

of all hospitalizations has been attributed to drug-

related diseases; 2 ⫺5% of all hospitalized types of

jaundice and 25% of all patients with acute necrotizing

hepatitis have been diagnosed as medication-induced

toxicosis. • A ten-year study carried out in Sweden

between 1966 and 1975 listed 274 deaths due to

pharmaceutical preparations, 23 (9%) of them with

toxic liver damage.

In Denmark, the incidence of

drug-induced side effects doubled within the space of

ten years (1978 ⫺1987).

In Japan, there was an 11-

fold rise in such side effects during a period of 30 years.

One French study gives the incidence of drug-induced liver damage as 13.9%.

• Various types of liver damage have been identified as resulting from some 1,000 medicinal preparations produced worldwide.

Acute liver failure may be caused by approximately 40 medicaments. The fatality rate was reported at 11.9%, whereby the risk of death did not differ significantly between hepatocellular and cholestatic patterns.

Over the past fifteen years, the incidence of drug- induced chronic hepatitis or cirrhosis has dropped to

< 10% due to the fact that “dubious drugs” are not administered so frequently and that there is greater care and prudence in drug usage. This also applies to certain other forms of damage, e. g. malignancy, VOD, ade- noma, FNH.

䉴 A comprehensive survey carried out in 1988 in a total of 2,008 medical practices in Germany found drug tox- icity in 12.4% of the 7,095 patients suffering from liver disease

: on average, the patients had been taking medication for approximately four years, with a max- imum period of regular intake of up to 30 years (!). In 32.4% of patients, the liver had been exposed to a

“double burden” as a result of the concomitant and regular daily ingestion of alcohol. The combination of two or more hepatotoxic drugs increased the risk con- siderably! This finding is of remarkable practical rele- vance. • In 1989 we conducted a renewed survey in an additional 2,990 medical practices (2,650 in Germany and 340 in Austria) and found that 17.7% of cases of acute liver disease in Germany and 14.3% of cases in Austria had been caused by drug toxicity, while 25.1%

of cases of chronic hepatic disease in Germany and 22.1% of cases in Austria were attributable to the intake of medicaments.

3 Pathogenesis

The pathogenesis of drug-induced liver damage is an individual, albeit multifactorial process. The main mech- anisms known to date include:

(1) Lipid peroxidation: Free radicals induce peroxidation of the unsaturated fatty acids of the ER. As a result, there is fatty degeneration of the liver, whereby the mitochondria and bio- membranes are damaged (possibly leading even to cell death).

(2) Oxidative stress: This process causes a depletion of glutathione in the hepatocytes with subsequent damage to (and even death of) liver cells.

(3) Inhibition of

β-oxidation: The enhanced formation of mito-

(4) Inhibition of protein synthesis: Some substances can inhibit RNA polymerase II and III (s. fig. 3.5). This in turn impairs the synthesis of enzymes, structural proteins and apolipoproteins.

The result is fatty degeneration of the liver and cell necrosis.

(5) Disorder of haem synthesis: Inhibition of hepatic coproporphy- rinogen-oxidase and uroporphyrinogen-decarboxylase can give

rise to secondary copro- and uroporphyrinuria or porphyria cutanea tarda.

(6) Inhibition of bile acid transport: More than 100 medicaments can cause intrahepatic cholestasis. In this case, the canalicular transport mechanisms are impaired. The retained bile acids damage the cells.

(7) Immunoallergenic reactions: Chemically generated neoantigens trigger a cytotoxic immune response to those hepatocytes that have such neoantigens on their surface.

(8) Carcinogenesis: Highly active or metabolically activated for- eign substances may form DNA adducts, which culminate in mutations, above all in the p 53 gene.

Drug metabolism in the liver is subject to numerous endogenic and exogenic influences. They interfere with various biotransformational reactions, alter the sensitiv- ity of the liver to drug products and determine the pattern of damage (see above).

(1) Non-variable factors are genetics, gender and age.

(2) Variable factors are coexisting diseases (diabetes, liver or renal disease, endocrinopathies), overweight, mal- nutrition (e. g. lack of protein), alcohol, additional medication, tobacco smoke particles, heavy metals and pregnancy as well as drug-related overdose, long- term intake or application form, etc. (s. tab. 3.18) Foreign substances, including medicinal products, are classified as obligate (directly effective) or as facultative (indirectly effective) hepatotoxins, depending on their degree of hepatic toxicity. Hepatotoxins are therefore grouped as either directly toxic or indirectly toxic according to the pathogenetic mechanisms of liver dam- age. Indirect hepatotoxins may, however, also cause an idiosyncratic type of liver impairment through immuno- logical or metabolic mechanisms.

(s. tab. 29.1) (s. fig. 29.1)

3.1 Obligate hepatotoxins

Direct hepatotoxins cause liver damage in all exposed persons (i. e. it is always predictable). They cause toxic damage. This direct toxic response occurs either because the hepatotoxic foreign substance cannot be detoxified at all or because detoxification by biotransformation does not proceed rapidly enough. Following a relatively short and usually stable latent period, the hepatotoxin directly effects the destruction of cellular structures, e. g.

by inactivating enzymes of the intermediary metab-

olism, by denaturation of cellular proteins or by lipid

peroxidation. (s. fig. 21.12) This leads to fatty infiltration

or necrosis of the liver cells. Obligate hepatotoxic medi-

caments are rarely clinically tested, since their hepatic

toxicity is normally recognized at an early stage in ani-

mal testing. However, negative results from tests carried

out on animals cannot guarantee absolute safety. This

has been demonstrated in the case of the preparations

benoxaprofen and ticrynafen, in which the respective

hepatic toxicity was only recognized after they had been

administered to “thousands of patients”.

Obligate

hepatotoxic pharmacons are only likely to be tested

clinically if their therapeutic benefit substantially out- weighs their hepatic toxicity (e. g. as an effective cyto- static agent). • Some medicinal preparations that were shown initially to be non-hepatotoxic may, however, become obligate (directly) hepatotoxic substances in overdoses ( ⫽ intoxification), as is the case with iso- niazid, mercaptopurine, methotrexate, paracetamol, tetracycline, etc.

3.2 Facultative hepatotoxins

In contrast, indirect hepatotoxins only cause liver dam- age in a small number of exposed persons (i. e. it is not predictable). There is an individual, situation-related propensity towards the biotransformational production of indirect hepatotoxins or a manifestation of individual hypersensitivity ( ⫽ idiosyncrasy). • Indirect toxic hepatic damage results from the interference of foreign sub- stance metabolites (which are, strictly speaking, bio- toxometabolites) with specific reactions of the inter- mediary metabolism. Such primary metabolic disorders include, for example, the alkylation or acylation of pro- teins, a lack of ATP or UTP, the blocking of receptors as well as of SH groups, or the binding to nucleopro- teins. Only at a subsequent stage do these disorders result in structural damage: steatosis or necrosis of liver cells, cholestasis and also tumour formation. This type of impairment displays the features of facultative hepato- toxins. • Idiosyncratic liver damage is caused by faculta- tive hepatotoxins. It only occurs in persons with a spe- cific hypersensitivity to the ingested foreign substance or to one of its metabolites. Idiosyncratic liver damage may take an immunological or a metabolic course.

In the immunological type of hepatotoxicity, the foreign substance or one of its metabolites is bound to a liver cell protein. This leads to the production of a hapten (antigen), which in turn triggers a humoral or cell-medi-

Criteria Hepatotoxic xenobiotics

• obligate • facultative ( ⫽ direct) ( ⫽ indirect) Liver damage

• directly toxic • indirectly toxic

• idiosyncratic

⫺ immunological

⫺ metabolic

1. Predictable toxicity ⫹ ⭋

2. Latent period short, long, varied

relatively stable (weeks 씮 months)

3. Dose dependency ⫹ ⭋

4. Reproducibility ⫹ ⭋

5. Evidence from animal ⫹ ⭋

experiments

Tab. 29.1: Pathogenetic criteria of hepa-

ated immune reaction and helps to detect autoanti- bodies, especially LKM-2 and LKM-3. Immunology- related liver damage is often accompanied by allergic symptoms (e. g. fever, exanthema, pruritus, arthralgia, eosinophilia) and by correspondingly identifiable histo- logical findings (granulomas, eosinophilic infiltrations).

• The metabolic type is reflected in an abnormal meta- bolic reaction, which occurs in a small number of exposed persons who are highly sensitive to the xeno- biotic or to one of its metabolites. In general, this abnor- mal type of metabolism is primarily a genetic disorder.

It results in the production of biotoxometabolites. This mechanism is thought to come into play with isoniazid and iproniazid, to name two examples. Symptoms of cholestasis are present, and AMA-M

positivity is fre- quently observed.

Idiosyncratic damage is also char- acterized by steatosis or necrosis of the liver cells as well as by a hepatitic reaction. (s. fig. 29.1)

However, these two types of damage resulting from facultative hepatotoxins do not explain all pathological metabolic effects, such as the occasional occurrence of allergens, mutagens, procar- cinogens, antivitamins and “new” toxins. (s. fig. 3.11)

•

two hypotheses are conceivable: on the one hand, these

4 Morphological reactions

4.1 Adaptive changes

The xenobiotic-related induction of the biotransformation system usually leads to an initial adaptive response:

hyperplasia of the

SER (⫽ smooth endoplasmic reticulum) occurs. (s. pp 55, 394,

ground glass hepatocytes (s. pp 114, 396,

Fig. 29.1: Diagram illustrating

1. Direct hepatotoxins

2. Indirect hepatotoxins

1. Metabolic type

2. Immuno- logical type

= Global = Partial

cell damage cell damage a. Selective

metabolic disturbances b. Selective

secretory disturbances

Necrosis Necrosis Cholestasis Necrosis

Steatosis Steatosis Necrosis Steatosis

Cholestasis Cholestasis Tumour formation I

Hepatotoxins

I I Idiosyncrasy I I I

Combined forms

but they may be evident as an unspecific finding in chronic hepa- titis B. The cytoplasm is fine-grained or fine-alveolate and looks pallidly eosinophilic. The nucleus, as well as the rough endoplas- mic reticulum, move to the clearly contoured cell membrane. Ani- sokaryosis and binuclear liver cells point to an

accelerated cell metabolism. In addition, giant mitochondria are sometimes present.

(s. fig. 28.3) (s. pp 395, 525)

If a sufficient level of adaptation cannot be achieved,

regressive alterations occur; homogeneous cytoplasm droplets are produced,

•

Single- cell necrosis may already be present in this border area, possibly

•

4.2 Morphological changes

Alterations in the liver parenchyma as a result of foreign substances are characterized by several parenchymal, mesenchymal and vascular basic reactions as well as by benign or malignant neoplasia. It seems reasonable to classify the morphological findings in accordance with the acuteness and chronicity of their occurrence ⫺ bear- ing in mind all fundamental and individual reservations with regard to their systematization. (s. tab. 29.2).

4.2.1 Steatosis

Microvesicular steatosis (s. p. 582) presents as deposits of tiny lipid

• Macrovesicular steatosis (s. p. 580) often

• Phospholipidosis is regarded as a spe-

Acute liver damage Chronic liver damage

Parenchymal findings

Parenchymal findings

• Steatosis • Chronic hepatitis

⫺ microvesicular • Cirrhosis

⫺ macrovesicular • Primary biliary cholangitis

⫺ phospholipidosis 2.

Inflammatory reactions

• Necrosis • Granulomas

⫺ single

3.

Vascular changes

⫺ focal

• Veno-occlusive disease

⫺ diffuse • Budd-Chiari syndrome

⫺ group necroses

• Cholestasis 4.

Fibrosis

⫺ canalicular 5.

Tumours

⫺ hepatocanalicular • Adenomas

• Jaundice ⫺ adenoma

2.

Vascular changes

• Intimal hyperplasia • Carcinomas

• Dilation of sinusoids ⫺ hepatocellular

• Peliosis hepatis ⫺ cholangiolar

• Portal vein thrombosis • Sarcoma

• Angiosarcoma 3.

Inflammatory reactions

• Infiltrations

4.

Combined forms

Combined forms

Tab. 29.2: Xenobiotic-induced acute and chronic types of morpho-

ids. Electron microscopy shows crystalline inclusions. This idiosyn- cratic hepatic lesion of the metabolic type has been observed for example during the administration of amiodarone. This substance has a long half-life and therefore remains in the liver for several months. Potentially fatal cirrhosis may occur. (s. p. 582)

4.2.2 Necrosis

Hepatocellular necrosis usually presents as coagulation necrosis. It is an aetiologically unspecific event that can have various causes, but it constitutes the most significant type of xenobiotic-induced hepatic damage. Cellular necrosis may affect either single cells or cell groups. (s. p. 400) A relatively characteristic feature of drug- induced toxicity are group necroses that are usually perivenously

localized, sometimes sector-like and accentuated, always clearly demarcated and often confluent. Idiosyncratic liver damage induced by halothane leads to necrosis affecting the entire liver lobule in a diffuse way. (s. fig. 29.2)

•

cell ballooning (s. p. 395) (s. fig. 21.4), which may

Fig. 29.2: Necroinflammatoric (“toxic”) hepatitis after halothane

4.2.3 Cholestasis

Xenobiotic-induced cholestasis is detected in three morphological types: (1.) intercellular in the form of

biliary thrombi, which are

bile droplets, which can be demon-

intercellular and intracellular cholestasis. (s. p. 229)

feathery degeneration of hepatic cells. (s. figs. 13.4;

22.4) (40, 63, 67, 73, 84, 91, 115) (s. tab. 29.10)

Occasionally, ductopenia (⫽ vanishing bile duct syn- drome) is observed. This condition is given when more than half of the portal fields in a large biopsy specimen fail to feature a bile duct. The irregular distribution of the lesions can make it very difficult to form a diagnosis based on just one biopsy specimen. The safest way is to carry out several biopsies (e. g. with the help of laparo- scopy) and to make an assessment based on more than 20 portal areas.

(s. tabs. 29.3; 29.10)

Jaundice: Hyperbilirubinaemia may be caused by drug-induced

Differential diagnosis must first rule out this haemolytic aetiology.

Jaundice (icterus) may be ascribed to various causes. (s. p. 218) Laboratory examinations and light microscopy have shown that several medicaments can (initially) cause a specific jaundice type, which continues in this same form until it disappears completely.

If the effect of the substance and the course of the jaundice persist, this drug-induced disorder can lead to cholestasis and morpho- logical changes. (24, 42, 47, 134)

Ajmaline Flucloxacillin

Amitryptyline Gold salts

Amoxycillin Haloperidol

Ampicillin Imipramine

Azathioprine Methyltestosterone

Barbiturates Norandrostenolone

Carbamazepin Perchlorperazin

Carbutamide Phenytoin

Chlorothiazide Promethazine

Chlorpromazine Tenoxicam

Cimetidine Tetrazycline

Clindamycin Tiabendazole

Cyclohexylproprionat Tiopronin

Cyproheptadin Tolbutamide

Erythromycin Trimethoprim

Estradiol Trioleandomycin

Tab. 29.3: Some medicaments that may provoke ductopenia (

Fig. 29.3: Mixed (intracellular and canalicular) cholestasis follow-

䉴 In a study of our own, we were able to demonstrate thiamazole-induced jaundice (maximum serum bilirubin 8.2 mg/dl with constantly normal values of AP, LAP and transaminases) over a period of more than five months.

(s. fig. 29.4)

Fig. 29.4: Pronounced bilirubinostasis and cholate stasis as well

4.2.4 Inflammatory reactions

The pattern of damage is as follows: steatosis, necrosis and cholestasis. They occur either as defined individual phenomena or (more frequently) in combination.

Depending on the severity and extent of these morpho- logical findings, two forms of inflammatory reaction are possible: (1.) mesenchymal reaction and (2.) cellular infiltration.

Mesenchymal reaction shows an activation of the stellate cell system; the stellate cells and the mononuclear phagocytosis system proliferate. (s. p. 397) Stellate cell nodules form. (s. fig. 22.3) This process spreads from the sinusoids at the site of the lesion to include neighbour- ing parenchymal cells. The reticular lattice fibre is dam- aged and sometimes even destroyed. • In a more massive lesion, the inflammatory process spreads to the portal zone; histiocytes, lymphocytes and eosinophilic leuco- cytes lead to portal zone cellulations with oedematous dilations, in some cases subsequent to portal fibrosis (s.

fig. 21.14), or to cholangitis of the PBC type (s. fig. 29.5) as well as of the PSC type.

Fig. 29.5: Slightly florid, destructive cholangitis (see arrow) resul-

䉴 The hepatic mesenchyma may also respond with the formation of granulomas.

(s. p. 398) This may well be the only morphological reaction provoked by foreign substances, although the formation of granulo- mas can sometimes be accompanied by the phenomena of steatosis, necrosis or cholestasis. From the pathogen- etic perspective, granulomas can be caused by direct toxic as well as idiosyncratic lesions. The formation of granulomas has been observed during the administra- tion of numerous pharmacons, e. g. sulphonyl urea. (s.

fig. 29.6) • Collidon (polyvinylpyrrolidon) is used in plasma substitutes. It is stored in Kupffer cells if the molecular weight is > 80,000. The substance has a yel- lowish-brown colour, which with HE staining presents as greyish-blue, coarse-grained pigment. Collidon is PAS-positive. Generally, it can only be detected six months after administration. (s. fig. 29.7)

Fig. 29.6: Epithelioid cell granuloma resulting from sulphonyl urea

Fig. 29.7: Collidon storage: resorptive reaction of Kupffer cells and

Cellular infiltration may vary in its degree, depending on the extent of the parenchymal lesion as well as on the type and duration of the toxic effect. A more severe inflammatory reaction corresponds to non-specific reactive hepatitis. (s. p. 392) (s. figs. 21.1; 29.8)

Fig. 29.8: Hepatic impairment with monocellular infiltration fol-

In this context, cell infiltrates consisting of leucocytes and lymphocytes can be found within the acinus and/or in the portal field; in contrast, in immunological-allergic impairment mechanisms, it is primarily lymphocytic and eosinophilic-leucocytic infiltrations that become manifest. This cellular reaction is also reversible.

4.2.5 Vascular reactions

Medicinal agents (such as contraceptives) may result in proliferations of the intima in the hepatic artery and its branches. In some cases, these arterial alterations were associated with thrombosis in the hepatic veins. • Phar- macons can trigger three different forms of damage to the sinusoids: (1.) dilation of the sinusoids (e.g. by con- traceptives), (2.) perisinusoidal fibrosis (e.g. by azathio- prine, vitamin A and cytostatic agents), and (3.) peliosis hepatis (e.g. by contraceptives, anabolic and androgenic steroids, azathioprine, chenodesoxycholic acid).

(s. p. 398) (s. fig. 21.8)

The hepatic veins may be affected by xenobiotic- induced occlusion resulting from thrombosis or from proliferation starting in the intima and subsequently producing (secondary) thrombosis. An occlusion of the large hepatic veins is known as the Budd-Chiari syn- drome. There are two distinct types, the truncular and the radicular form, the latter corresponding to veno- occlusive disease. (s. p. 249) Contraceptives

and cytostatic agents are held responsible.

Women develop this type of hepatic disease more than twice as often as men. (s. fig. 29.9)

Fig. 29.9: Budd-Chiari syndrome with obliterated radicular vein

tab. 29.10)

Occlusion of the small hepatic veins is called veno-occlu- sive disease (VOD)

;

. It is identical to the radicular type of the Budd- Chiari syndrome. (s. p. 249) Cytostatics and azathio- prine are among the alleged causal agents.

Diagnosis is based on imaging techniques (ultrasound, CEDS, CT), and sometimes on liver biopsy. (s. fig.

29.10) (see chapter 39)

Fig. 29.10: Intima proliferation and thrombosis of a (radicular)

4.2.6 Liver tumours Benign tumours

As regards the neoformation of benign tumours, distinc- tion is made between nodular adenoma and focal nodu- lar hyperplasia (FNH). Because there are several transi- tional types between these two forms, they are generally regarded as variants of the same basic type of tumour

(H.-W. Altmann, 1980)

. Both types may be multiple. (s.

tab. 29.10)

Diagnosis: Benign hepatic tumours triggered by medica- ments are generally diagnosed at a late stage or coinci- dentally during abdominal sonography. The tumour develops asymptomatically over an extended period of time. • Symptoms only appear when the tumour has grown to a certain size: upper abdominal pressure and occasional pain radiating to the back or to the right shoulder. This may point to tumoural bleeding, the for- mation of subcapsular haematoma or impending rup- ture. A rupture is accompanied by the obvious signs of acute abdomen and the symptoms of haemorrhagic shock (possibly with simultaneous abdominal trauma, straining or retching). • Diagnosis is possible by ultra- sound and other imaging techniques (if necessary, with contrast medium). Laparoscopy also provides a reliable diagnosis. If at all, biopsy is only indicated by laparos- copy and using a fine needle or Robbers forceps (there is a possible danger of bleeding due to the high degree of vascularization). • Values beyond the normal labora- tory parameters (bilirubin, AP, LAP, GPT, cholinester- ase, etc.) are only evident once the tumour has reached a certain size. We have found subnormal or very low GGT values in almost all women taking oestrogen.

Increased γ-GT values were accompanied by the onset of cholestasis. (see chapter 36)

Adenoma: The potential association of hepatic adenoma

with the long-term use of oral contraceptives was first

suggested by

in 1973. Although the detec-

tion of adenoma was extremely rare before 1954, more

than 400 cases were published by 1985. This figure has

probably risen even further, but such findings have sel-

dom been published since that time, as the diagnosis was often deemed not worth reporting. Thanks to the ultrasound technique, which is now used on a routine basis, hepatocellular adenomas rarely escape detection today. Most of them are located close to the surface.

(We have data on 8 unpublished cases) (s. fig. 29.11)

Fig. 29.11: Adenoma (approximately 5 cm in diameter) following

Focal nodular hyperplasia: FNH is the most common benign hepatic neoplasia. As with adenoma, it may develop after the patient has taken oestrogens for a longer period (usually more than 4 or 5 years). In some cases, the lesion develops within 6 to 12 months after intake begins.

When the oral contraceptives are discontinued, the tumour regresses or disappears (com- pletely). The rate of both oestrogen-induced hepatocel- lular adenoma and FNH was considerably reduced after the introduction of low-dose oral contraceptives.

Fig. 29.12: Focal nodular hyperplasia in the left liver lobe follow-

Fig. 29.13: Focal nodular hyperplasia with parenchymal nodules

A genetic predisposition is assumed on the basis of fre- quency within families. The liver-damaging effect seems to be closely connected to the C

and C

steroid ring and alkylation in the 17 α-position. Even the simulta- neous occurrence of an adenoma and FNH under oestrogen administration has been described.

While there is a clear connection between adenoma formation and the intake of oestrogens, the association between FNH and oestrogens, albeit plausible, still lacks confirmation. However, our own observations strongly suggest a causal relationship. (s. figs. 29.12, 29.13) FNH may also be caused by azathioprine, clofi- brate and nitrofurantoin.

Malignant tumours

Evidence that focal nodular hyperplasia tends to degen- erate into malignant tumours is still lacking. • Hepato- cellular adenomas pose the (rare) risk of developing into hepatocellular carcinoma

. Several cases have been published in recent years.

We can add our own observation here. (s. fig. 29.14)

Fig. 29.14: Liver cell adenoma after 21 years’ use of oestrogens,

䉴 A 60-year-old female patient was referred to us for differential diagnosis of cholestasis after having taken oestrogen for about 21 years (substitution following bilat- eral removal of polycystic ovaries): AP 206 U/l, LAP 52 U/l, γ-GT 7 U/l (!), GPT 42 U/l, GOT 32 U/l, GDH 12 U/l, copper 192 µg/dl, cholinesterase 2,150 U/l. Repeated measurements consistently provided normal values for 움

- foetoprotein; haemogram, LDH, iron, etc. were normal;

demonstration of adenoma by ultrasound and CT, but with additional “unclear structures.” Laparoscopy confirmed the adenoma, together with several subcapsular bleeding foci and hepatocellular carcinoma (identified by forceps biopsy).

In contrast to primary hepatocellular carcinoma, the 움

- foetoprotein values are normal

, which is also true of the case we presented above. In opposi- tion to this, a rapid increase and significant rise in AFP values have been reported. Metastasis formation is rare and always relatively late. • It has been observed that hepatocellular carcinoma can follow the intake of hor- mone-based contraceptives as well as long-term admin- istration (several years) of 17 α-alkylated androgenic, anabolic steroids and methotrexate. Cholangiocarcinoma may also be caused by the long-term intake (several years) of hormone-based contraceptives, androgenic agents and α-methyldopa. The formation of angio- sarcoma has likewise been attributed to the long-term use of oral contraceptives, oestrogens, androgenic and anabolic drugs. (s. tab. 29.10)

Diagnosis: Malignant tumour formation is accompanied by inappetence and weight loss, pain in the upper right abdominal quadrant, fever, specific laboratory findings and paraneoplastic symptoms. (see chapter 37)

4.2.7 Fulminant liver failure

Fulminant or protracted liver failure is caused by medi- caments in 10 ⫺15% of cases. A reduction in the func- tional liver mass to < 20 ⫺35% is deemed to be a critical stage. However, the death of the patient may already occur due to secondary metabolic disorders (so-called exogenous hepatic coma) before the extent of the paren- chymal loss has fallen below the critical threshold (so- called endogenous hepatocellular disintegration coma).

(s. tab. 29.10)

Three forms of drug-induced liver failure are distin- guished: (1.) obligate, dose-dependent toxicity (e. g. para- cetamol, (s. fig. 20.3), (2.) unpredictable, idiosyncratic liver insufficiency (e. g. isoniazid), and (3.) immunoaller- gic idiosyncrasy (e. g. halothane) (s. fig. 29.2).

Initially, unspecific complaints frequently include nau- sea, inappetence and fatigue. • In some patients, idiosyn- cratic hepatocellular damage may be accompanied by hypersensitive reactions (e.g. fever, exanthema, eosino- philia, lymphocytosis, arthralgia).

Obligate, dose-dependent drug-induced toxicity need not be feared, since substances which predictably cause severe toxicity are not usually applied as medical reme- dies. It is only in cases where the therapeutic effect clearly outweighs the known type of damage that an obligate toxic substance is administered as a therapeutic agent ⫺ but in accordance with strict criteria!

It should be mentioned that almost all cases of fulmi- nant or protracted liver failure caused by a certain sub- stance are isolated occurrences that cannot be foreseen.

They develop as a result of individual idiosyncrasy despite correct dosage and observation of all possible interactions. (s. tab. 29.4)

Acarbose Labetalol

Allopurinol Leflunomide

Amiodarone Lisinopril

Amphotericin B MAO inhibitor Antirheumatics Methotrexate

Benoxaprofen Methyldopa

Bromfenac

Minocycline

Carbamazepine Nefadozone

Clozapine

Nibutamid Cotrimoxazole Nimesulide

Cyproterone Niperotidine

Cytostatics Ofloxacin

Diapsone Omeprazole

Dicoumarol

Paracetamol

Didanosine Pemoline

Dideoxyinosine Phenhydrane Disulfiram

Phenprocoumon

Ebrotidine Phenytoin

Ecstasy

Pirprofen

Enflurane Probenecid

Etoposide Prophylthiouracil

Exifon Pyrazinamide

Fluconazole Rifampicin

Flutamide Rosiglitazone

Gemcitabine

Sulphonamide

Halothane Tetrabamate

Hydroxychloroquine Tetracycline

Ibuprofen Triazolam

Imipramine Tolcapone

Interferon- α Troglitazone

Isoflurane Usnic acid

Isoniazid Valproic acid

Ketoconazole Zoxazolamine

Tab. 29.4: Some medicaments that may provoke idiosyncratic ful-

The mortality rate depends on the cause of disease, the patient’s age as well as the intensity and duration of encephalopathy. Since the introduction of liver trans- plantation and temporary liver-supporting systems, the mortality rate in acute liver failure has been reduced markedly.

The initial diagnosis is based mainly on the determin-

ation of laboratory values, which can be used as starting

point for assessing the further course of disease. • The same applies to sonography as regards the determination of liver size and echo structure. Liver size can also be determined exactly by means of CT. (s. tab. 29.5)

䉴 GC protein (group-specific component) is an α2-globulin which is synthesized in the liver and which binds actin released due to hepatocyte decay. Decreased GC-protein values in the plasma are thus attributable both to its reduced synthesis in acute liver failure and its increased binding to actin as a result of hepatocellular disintegration. A value of < 34µg/ml was associated with a lethal outcome in some 70% of cases.

Basic diagnostics Coagulation

haemogram Quick’s value

urine analysis AT-III

electrolytes T-AT-III complex

glucose factor II, V

blood gas analysis LDH

Liver Kidney

GPT, GOT, GDH urea

bilirubin creatinine

cholinesterase GC protein

Sonography

CT

Tab. 29.5: Diagnostic measures in suspected fulminant liver failure

5 Clinical aspects

Liver damage caused by drug-induced toxicity, more specifically the intrahepatic obstructive type of jaundice resulting from the intake of arsphenamine, was first described by

in 1940.

5.1 Clinical courses

Toxic liver damage does not produce a characteristic clinical picture. It is determined by the underlying lesion pattern. Clinical courses range from asymptomatic to symptomatic and from acute to chronic.

앫 asymptomatic 앫 symptomatic

1. acute 씮 normalized 2. acute 씮 chronic 3. chronic 씮 chronic 4. chronic 씮 normalized

씮 healed with residual fibrosis Drug-related hepatic damage can mimic almost any liver disease and must, therefore, always be included in the differential diagnosis. (s. tab. 29.6)

1.

Jaundice type

⫺ bilirubin 앖 2.

Cholestasis type

⫺ AP, LAP, γ-GT 앖 3.

Jaundice-cholestasis type

⫺ bilirubin, AP, LAP, γ-GT 앖 4.

Fatty liver type

⫺ γ-GT 앖, perhaps GPT, ChE 앖 5.

Hepatitis type

⫺ GPT, GOT, GDH, γ-GT 앖 DeRitis quotient⬍1 6.

Cholestatic hepatitis type

⫺ GPT, GOT, GDH, γ-GT, AP 앖 7.

Necrosis type

⫺ GPT, GOT, GDH 앖 DeRitis quotient⬎1

generally bilirubin, AP,γ-GT 앖; ChE, Quick 앗 8.

Cholangitis type

⫺ GPT, GOT, GDH, γ-GT, AP 앖 possibly bilirubin앖, ChE 앗 possibly autoantibodies⫹ 9.

Chronic hepatitis type

Cirrhosis type

Fibrosis type

Vascular type

Tumour type

Combined forms

Tab. 29.6: Morphological reactions or laboratory findings result-

29.10)

Thus a pure jaundice type can occur with unconjugated hyperbilirubinaemia, or a cholestasis type is witnessed, which may or may not be accompanied by simultaneous jaundice. (s. figs. 29.3, 29.4) The fatty liver type often starts out uneventfully with no abnormal laboratory values until increased levels of γ-GT and, in several cases, an additional rise in GPT and ChE occur. The hepatitis type with greatly varying laboratory values also produces a clinical picture with multiple interpretations:

it may present as acute hepatitis, protracted or persistent hepatitis, non-specific reactive hepatitis or “granuloma- tous” hepatitis. The liver damage may progress as a cho- lestatic hepatitis type, necrotic type (s. fig. 29.2) or cho- langitis type (s. fig. 29.5), with the corresponding indicative laboratory findings. • Chronic courses include chronic active hepatitis type, cirrhosis type and fibrosis as well as vascular or tumour type. • Combined forms of damage are also frequent. Their diagnostic categoriza- tion presents considerable difficulties. (s. tab. 29.6) 5.2 Anamnesis

Sometimes, there are no complaints at all. Mostly, how- ever, patients have atypical complaints, which are possi- bly suggestive of toxic liver damage:

common cold fever nausea

diarrhoea lack of appetite pruritus

lacrimation

5.3 Clinical findings

The following clinical findings can be considered as additional symptoms for the detection of liver damage caused by drug-induced toxicity:

abdominal pain leucocytosis/leucopenia

arthralgia lymphadenopathy

conjunctivitis myalgia eosinophilia rhinitis

exanthema scratching

5.4 Laboratory findings

The focus is on determining γ-GT as an indicator of long-term (several weeks) intensive activation of the biotransformation system as a result of drug intake ⫺ once other causes of elevated γ-GT have been excluded.

(s. p. 97) Generally, the γ-GT level remains normal dur- ing the intake of oral contraceptives or long-term con- tact with halothane (values are even subnormal in patients taking oestrogen). • A rise in GPT (usually also in GOT) suggests the development of drug-induced hepatocellular damage. Generally, a so-called inflamma- tory type (DeRitis quotient < 1) can be identified. (s. p.

95) In this context, γ-GT is regarded as the screening enzyme for drug-related activation of the biotransfor- mation system, and GPT is seen as the screening enzyme for the resulting liver damage. • Decreased levels of cholinesterase point to a reduction in ChE synthesis in the area of the rough endoplasmic reticulum due to drug-related toxicity. Intake of hormone-based contra- ceptives likewise leads to diminished ChE activity. (s. p.

103) • The increase in AP suggests a toxic hepatic lesion of the cholestasis type (with or without jaundice), pos- sibly with simultaneously augmented or normal GPT (and GOT). (s. p. 101) • This so-called threefold pattern ( γ-GT, GPT, ChE) is regarded as an efficient and rational test to demonstrate hepatic damage with a sen- sitivity of approx. 95%. Cholestasis is detected by the fourfold pattern (γ-GT, GPT, ChE, AP) with a sensitiv- ity of approx. 96%. (s. p. 103) (s. tab. 5.11) Additional diagnostic findings can be generated from the enzyme ratios. (s. p. 95) (s. tabs. 5.6, 5.7; 29.5, 29.6)

Evidence of autoantibodies, such as ANA, AMA and SMA, points to the immuno-allergic pathogenesis of drug-induced liver damage. These autoantibodies can be detected both singly and in a combined form. Usually, they occur in low titres. As a rule, they have been found with clometazine, fenofibrate, oxyphenisatin, papaver- ine, etc. Anti-LKM 2 was detected after the administra- tion of ticrynafene, and anti-LM after dihydralazine.

(The subgroup AMA anti-M

was identified as a specific antibody following the intake of iproniazid

; it has not been found since iproniazid was taken off the mar- ket). However, autoantibodies are of no diagnostic value in medication-induced liver damage.

5.5 Search for causes

In most cases, the search for the causal toxin must be carried out with detective-like meticulousness. However, neither in the physician’s practice nor in the hospital can this search be conducted with the required precision, since the time available is not sufficient to establish the individual medication history in depth, or the patient is generally agitated and cannot answer detailed and direct questions satisfactorily. Drug- and/or chemical-related anamneses are often incomplete or unreliable, because the patient was not given sufficient time at the doctor’s surgery and was not able to take a close look at the medicines kept at home in order to provide more precise answers. • For these reasons, our check-list, which is given to the patient in the form of a questionnaire, has proved to be of great assistance over many years. (s.

tab. 29.7)

Intake via

䊊 mouth 䊊 skin

䊊 inhalation 䊊 blood vessels

Since when? Until when?

How much? How often?

1.

Medication?

2.

Hormones? (oral contraceptive, etc.)

3.

Chemicals? (job, hobby, home, garden, environment)

Alcohol?

5.

Drug abuse?

6.

Cosmetics? (after-shave, personal hygiene products)

Tonics?

8.

Aphrodisiacs? (potency drugs)

Premixed herbal teas?

10.

Food preservatives? Special foodstuffs?

11.

Body contact with chemicals? Synthetics?

12.

Journeys abroad?

Tab. 29.7: Check-list for the detection of possible hepatotoxic

Very few terms in this questionnaire require further

explanation, and we also include some brief instructions

about how to answer the questions. The patient has suf-

ficient time to think about the individual questions

either at home or in the hospital, is able to consult fam-

ily members and may even take several days to complete

the questionnaire. While discussing the responses with

the doctor, further information can be added. This may

require repeated and sometimes outright “inquisitory

questioning”, as the patient (1.) may have forgotten to

mention certain medicaments or may not consider them as such (e. g. laxatives), (2.) may be ashamed to admit taking or abusing certain agents (e. g. aphrodisiacs ⫺ sometimes of rather obscure composition), (3.) may fear detection or may not wish anyone to know (e. g. abuse of drugs, alcohol, analgesics or soporifics), or (4.) may also consciously (or subconsciously) repress the prob- lems connected with toxic liver damage in line with a generally increasing tendency towards self-medication and a firm belief in tablets.

However, it must be considered that it is often only the combined intake of medicaments, alcohol and other chemical substances that gives rise to such biotoxometa- bolites, which do not form when the respective sub- stance is taken on its own.

䉴 Discrepancies between pathologically altered labora- tory parameters and minor or uncharacteristic histo- logical changes, or even normal findings in the biopsy specimen, are regarded as almost typical for liver dam- age resulting from drug-induced toxicity. • In individual cases, however, the histological findings can be attri- buted to a specific chemical substance once the toxin has been identified. • As a rule, laboratory and morpho- logical findings are all the more distinctive when the hepatic detoxification mechanisms have been constantly used and are ultimately exhausted.

5.6 Herbal remedies

Remedies prepared from herbal extracts have been used by all peoples since ancient times. • In recent years, herbal remedies have enjoyed growing popularity in modern societies. This trend can be explained by the following factors: (1.) ecological movements in industri- alized states call for a return to natural products, (2.) there is a widespread naive opinion that a natural prod- uct cannot be anything else but a good product, and (3.) it is commonly believed that unlike chemical prepar- ations, herbal remedies are free of side effects.

Apart from the therapeutic effect, the special active agent can at the same time act as a facultative hepato- toxin in individual cases. • Furthermore, the production of herbal remedies may involve certain errors and risks which can be crucial factors in the development of liver damage. (s. tab. 29.8)

1. Misidentification of the medicinal plant 2. Contamination of the plant

⫺ e.g. chemicals, heavy metals, microorganisms 3. Use of unsuitable or wrong parts of the plant

4. Variations in the formation of active plant substances due to different conditions of growth

5. Adulteration of active agents during conditioning 6. Mislabelling of the end product

Tab. 29.8: Certain errors or risks involved in the preparation of

It is difficult to clarify the hepatotoxicity of herbal remedies, especially if they are comprised of a mixture of several plants or various components of the plant.

Moreover, herbal remedies are often applied as automedication, and patients withhold the information that they have used them. (s. tab. 29.9) (s. fig. 29.15)

Plants containing pyrrolizidine alkaloids

⫺ Crotalaria

⫺ Heliotropium

⫺ Senecio

⫺ Symphytum officinale

앫 These alkaloids are the main cause of VOD

Reported hepatotoxicity Hepatitis Necrosis ALF

Atractylis gummifera ⫹ ⫹ (R)

Callilepsis laureola ⫹ ⫹ (R)

Cassia angustifolia ⫹

(Senna)

Chinese herbs ⫹ ⫹ (R)

Larrea tridentata ⫹ (R)

(Chaparral) (35, 56, 106)

Lycopodium serratum ⫹

(Jin Bu Huan) (89) ⫹ (R)

Pennyroyal ⫹ ⫹ (R)

(Hedeoma pulegioides) (Mentha pulegium) Piper methysticum (Kava) (99, 116)

Teucrium chamaedrys ⫹ (R)

(Germander) (26, 91)

Suspected hepatotoxicity

Azadirachza indica Teucrium polium Berberis vulgaris Valeriana officinalis Scutellaria lacteriflora

etc.

Tab. 29.9: Medicinal plants with reported or suspected facultative

Fig. 29.15: Chronic toxic hepatitis after 10 months chaparral

Information about the effectiveness or safety of herbal remedies is based on experience transmitted over cen- turies rather than on controlled trials or toxicity studies.

Numerous medicinal plants have been reported to pos- sess facultative hepatotoxicity, or there is suspicion thereof.

Kava extracts can, if overdosed (> 60 ⫺120 mg kavapyr- ones/day) and/or taken over a longer period (> 3 months), cause hepatotoxicity in the form of hepatic reactions and liver cell necrosis; in rare cases, they may even cause cholestasis and acute liver failure (possibly leading to liver transplantation). Risk factors include the concomitant intake of medicaments and alcohol as well as a genetically based deficiency of cytochrome P 450 2 D6.

5.7 Test procedures 5.7.1 Withdrawal trial

The elimination of the causal noxa leads to an improve- ment in the pathological laboratory values, which repre- sents an important diagnostic finding. This procedure constitutes the most significant therapeutic measure. • If various medicaments or substances are suspected to have caused the damage, one noxa after the other should be discontinued, and the effect of discontinu- ation on laboratory parameters should be tested after four to six weeks. The causal noxa normally “reveals itself ” during this test. The drugs shown to be non-toxic can then be administered again, although laboratory parameters should be tested continuously to rule out any “false diagnosis”. If a false diagnosis is established, the procedure (i. e. diagnostic and therapeutic with- drawal trial) will have to be repeated. • When hepatotox- icity due to home- or workplace-related exposure is sus- pected, laboratory parameters should be tested just before the patient goes on holiday as well as immediately after his/her return. This is of special significance if the patient is absent from work and/or home for at least 2 or 3 weeks. • Alcohol intake, in any form or quantity, must be prohibited during the withdrawal trial. This also applies to holiday trips that are intended to be used for such a test. • Reliable results can only be achieved if the patient complies fully with the stringent requirements of a withdrawal trial and cooperates well!

5.7.2 Re-exposure trial

䉴 Re-exposure trials are regarded as unacceptable because dangerous exacerbations may occur. In add- ition, negative re-exposure trial results would not suffice to rule out drug-related liver damage completely.

At present, there are no biochemical methods that facilitate early and reliable identification of the drug- induced toxicity which causes the liver damage.

6 Prognosis

Patients with liver damage resulting from medicament- induced toxicity generally have a good prognosis.

Changes regress completely after discontinuation of the implicated drug. However, it may take several weeks or months for the laboratory values and morphological findings to normalize. • Changes in the connective tissue remain (unless there is spontaneous reversal). These alterations appear histologically as fine periportal or periacinous fibroses

, and laparoscopically as delicate, partly reticular fibroses, perivascular connective tissue or as a finely pimpled hepatic surface. (s. figs. 28.7, 28.10) • Vessels affected by thrombosis generally remain closed unless spontaneous thrombolysis or recanalization occurs. • The mortality is high for acute necrosing types of damage (e. g. 30 ⫺50% of halothane-induced cases). The prognosis may also be poor when various toxins take effect at the same time. The disease can progress, even though the causal toxin has been eliminated. An auto- immune process may have been triggered, or another chemical substance may have taken over the function of the eliminated causal noxa.

7 Therapy

䉴 Liver damage may not only be caused by a certain substance, but also by an interaction of a combina- tion of substances (e.g. multi-drug therapy, numerous constituents in plants) ⫺ moreover, this can happen in different individual ways.

The treatment of drug-induced liver damage comprises a wide range of measures. • (1.) Discontinuation of the implicated noxa is regarded as the most effective ther- apy. • (2.) In cases of acute intoxication, elimination of the noxa from the body is essential (e.g. gastrointestinal lavage, forced diuresis) (s. p. 572!) • (3.) In certain intoxi- cations, the application of an antidote is required (e.g.

N-acetylcystein, silibinin, deferoxamine) (s. pp 383, 571, 625). • (4.) In the case of lipid peroxidations, it is not known precisely to what extent a therapeutic effect is achieved by adjuvant treatment with antioxidants. (s. p.

67) • (5.) This also applies to adjuvant efforts to treat

drug-induced cholestasis by reducing toxic-hydrophobis

bile acids (e.g. lithocholic acid) with the help of urso-

deoxycholic acid. The use of S-adenosyl-L-methionine

has been considered in this context. (s. p. 241) • (6.) In

rare cases, the use of glucocorticoids may be indicated. •

(7.) Symptomatic measures may be undertaken in indivi-

dual cases. They include increased intake of fluids and

vitamins as well as electrolytes (if required). • (8.) In

patients with severe courses and also in the Budd-Chiari

syndrome, the therapeutic measures are the same as in

acute liver failure. (s. pp 382 ff.)