Diagnostic and therapeutic approach to cholestatic liver disease

T. Pérez Fernández, P. López Serrano, E. Tomás, Mª L. Gutiérrez, J. L. Lledó, G. Cacho, C. Santander
and C. M. Fernández Rodríguez

Unit of Digestive Diseases. Fundación Hospital Alcorcón. Madrid, Spain

 

ABSTRACT

When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatiic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP) or trans-hepatic cholangiography (THC) should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some especific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hiperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a mid-dle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, α₁-antitripsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered.

Key words: Cholestasis. Ultrasonography. Cholangiography. Pruritos. Ursodeoxycholic acid.

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Pérez Fernández T, López Serrano P, Tomás E, Gutiérrez ML, Lledó JL, Cacho G, Santander C, Fernández Rodriguez CM. Diagnostic and therapeutic approach to cholestatic liver disease. Rev Esp Enferm Dig 2004; 96: 60-73.

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Recibido: 09-07-03.
Aceptado: 16-07-03.

Correspondencia: Conrado M. Fernández Rodríguez. Unidad de Aparato Digestivo. Fundación Hospital Alcorcón. Avda. Budapest, 1. 28922 Alcorcón, Madrid. Telf.: 91 621 95 13. e-mail: cfernandez@fhalcorcon.es

 

INTRODUCTION

Cholestasis can be defined as a clinical and biochemical syndrome caused by an impaired bile flow often associated with clinical manifestations such as jaundice and itching, and biochemical disturbances such as elevated alkaline phosphatase levels (1).

Cholestasis is further classified as intrahepatic, when the anatomical location of the impairment in bile excretion is somewhere between the hepatocellular cytoplasm and medium-size bile ducts (up to approximately 400 mm in diameter), and extrahepatic when it occurs in the great bile ducts, which is commonly caused by calculi, pancreatic and biliary tumors or hilar lymph nodes metastasis (1).

INTRAHEPATIC CHOLETASIS CONDITIONS

1. Most cases result from inflammatory and destruc-tive conditions affecting intrahepatic bile ducts, which is designated as “vanishing bile-duct syndromes”:

A. Primary biliary cirrhosis (PBC) is the best known condition in this category. Progressive, non-suppurative inflammation and destruction of interlobular bile ducts characterizes PBC. It occurs predominantly in women (female to male ratio 9:1), usually between 40 and 60 years of age (2).

A salient feature of this syndrome is the presence (up to 95% of patients) of antimitochondrial antibodies (AMA). These antibodies are directed against the pyruvate dehydrogenase complex (PDC) of the inner mitochondrial membrane (E2). The autoantigens gp210, p62, Sp100 and PML have also been recognized to be specifically linked to PBC (3,4). Although these antibodies have not been shown to be directly involved in the pathogenesis of PBC, autoimmunity is thought to play a major role. It has been postulated but not confirm-ed that infectious agents may underlie the pathogenesis of PBC, as protein E2 has been recognized in bacteria and other infectious agents in the urinary tract of women (3).

B. Primary sclerosing cholangitis (PSC) is, like PBC, a progressive cholestatic disorder of unknown etiology characterized by inflammation, fibrosis and scattered stricturing of medium and large size ducts in the intrahepatic and extrahepatic biliary tree. Patients with PSC are more likely to be men, the average age at diagnosis is 40 years (5), and the disease is often associated with inflammatory bowel disease (IBD) (6). Several pathogenetic mechanisms have been postulated in PSC. These can be broadly divided into non-immune factors (such as portal bacteremia, viral infections, toxins, and ischemic injury) and genetic/immune factors. A high prevalence of the perinuclear antineutrophil cytoplasmic antibody (pANCA), between 26 and 85 per cent, has been reported (4).

C. Autoimmune cholangiopathy (AC). In contrast to PBC, patients with autoimmune cholangiopathy have negative AMA but positive ANA, and clinical features and liver histology are consistent with PBC. In addition, antibodies against a subtype of carbonic anhydrase (CA-II), an enzyme present in the bile duct epithelium, are frequently found (7,8). Autoimmune cholangiopathy must be distinguished from overlap syndromes (PBC/ HAI and PSC/HAI).

D. Idiopathic adult ductopenia predominantly affects young adults with clinical and biochemical evidence of cholestasis. The hallmark of this disease is the loss of interlobular and septal bile ducts in more than 50% of the small portal tracts (9,10).

E. Allograft rejection (11).

F. Graft-versus-host disease (GVHD).

In both situations cholestasis resulting from intrahepatic bile duct destruction may develop. In GVHD small bile duct cells are the primary target of injury in the liver (12).

G. Lymphoma: about 10% of patients develop jaun-dice, and early and often progressive ductopenia and periductular fibrosis are found (13).

2. Choletasis is related with liver toxics or metabolic disorders in many ocassions.

A. Drug-induced liver injury occurs through an inhibiton of metabolic processes or immunoallergic reactions. Occasionally the histologic pattern may evolve to ductopenia, which reminisces changes observed in PBC (14,15). Although nearly any drug may cause cholestasis, table II lists some commonly prescribed drugs that may result in cholestasis.

B. Cholestasis of pregnancy. There are two general types of disorders: a) hyperemesis gravidarum; and b) intrahepatic cholestasis of pregnancy (13).

C. Total parenteral nutrition (TPN). The mechanism by which parenteral feeding causes cholestasis is unclear, but it may be associated with several causes: concentrated solutions of glucose and aminoacids that can diminish bile flow; absence of oral food intake associated with decreased excretion of bile acid; intestinal bacterial overgrowth, sepsis and drug toxicity, which may also be present in these patients (11).

3. Infectious conditions. The reported prevalence of cholestasis in patients with septicaemia of non-biliary origin ranges between 1 per cent and 34 per cent. Cholestasis results from the effects of bacterial toxins and pro-inflammatory cytokines, which may affect bilirubin transport, increase biliary permeability, and reduce bile flow and bile acid uptake (1).

4. Histological features of cholestasis also are common in:

A. Acute viral hepatitis. Prolonged cholestasis has been described in association with hepatitis A, hepatitis B and CMV infection. About 20% of patients who undergo liver transplantation for chronic hepatitis B develop cholestatic fibrosing hepatitis, with marked hyperbilirubinaemia and progressive hepatocellular failure (17).

B. Cholestasis may be the major presenting feature in autoimmune chronic active hepatitis and in alcoholic hepatitis.

5. Benign recurrent intrahepatic cholestasis. This is a rare disorder, characterized by recurrent episodes of unexplained cholestasis separated by long asymptomatic periods. In some families the condition is inherited as a recessive disorder (18).

6. Hepatic infiltration. Some conditions may cause intrahepatic cholestasis due to deposits in liver. About one-third of cases of primary amyloidosis have clinical or biochemical evidence of liver involvement, and 5% develop cholestatic jaundice (1).

CLINICAL MANIFESTATIONS OF THE CHOLESTATIC SYNDROME

The clinical and biochemical features of the cholestatic syndrome result from an accumulation of substances in the liver, blood and other tissues that are normally excreted in bile, and malabsorption of fat and fat-soluble vitamins as a result of inadequate postprandial bile-acid concentrations in the upper small intestine. Clinical features included pruritus, jaundice, xanthomas, diarrhoea, fat-soluble vitamin deficiency or osteoporosis (Table III). Most chronic cholestatic conditions may progress towards cirrhosis (11,19,20).

DIAGNOSTIC EVALUATION OF SUSPECTED CHOLESTATIC DISEASE

Figure 1 illustrates a logical diagnostic approach to patients with cholestasis. When confronting a patient with cholestasis, the first steps in the diagnostic evaluation are: a) assesment of past medical history, drug therapy, herbal remedies, risk of viral hepatitis, and alcohol abuse; and b) family history. Laboratory abnormalities should be confirmed before starting an extensive diagnostic work-up (4,20).

Abdominal ultrasonography is necessary to exclude extrahepatic biliary obstruction. If there is sonographic evidence of biliary obstruction, then colangiography is indicated. ERCP stands for the best option if endoscopic treatment is probable; otherwise, cholangio-MRI is indicated. If jaundice is mild (usually <12 mg/d), and right upper quadrant pain, fever or a history of biliary colic are present, choledocal stones is the most likely diagnosis. In contrast, when painless, progressive jaundice (usually >12 mg/dl) associated with weigth loss, a palpable gallbladder or an abdominal mass are present, a malignant biliary obstruction should be strongly suspected.

Once extrahepatic biliary obstruction is excluded, the clinical setting is important in orienting the diagnosis, as occurs in cholestasis associated with pregnancy, with parenteral feeding or with bone marrow/liver transplant. Intake of drugs, specially in the last 6 months, should be recorded and discontinued. Follow-up is indicated (11). If alcohol abuse and evidence of chronic or decompensated liver disease are present, alcoholic hepatitis is the most likely diagnosis, whereas positive risk factors point to viral hepatitis.

The initial laboratory work-up should include liver chemistry, viral serology, and a screening for autoantibodies (3). A positive AMA with a titration greater than 1/80 in a female over 40 years of age points to PBC, and a liver biopsy should be considered (21). PBC diagnostic criteria include: a) serum ALP levels at least twice as high as the upper limit of normal values; b) a positive test for AMA; and c) a liver biopsy specimen showing florid bile duct lesions. In most cases a diagnosis is made while investigating raised serum ALP and/or antimitochondrial antibodies. A liver biopsy is not necessary for the diagnosis when clinical/laboratory data are positive in a middle-aged female patient (22).

When the AMA test is negative with positive ANA and/or ASMA, autoimmune cholagitis should be considered, and an ERCP is indicated to exclude a PSC, al-though this is more likely in young men with IBD (4). AMA-negative patients with normal cholangiography are considered to have AMA-negative PBC or autoimmune cholangitis. The features of the liver biopsy will help confirm the diagnosis.

If cholangiography is abnormal, PSC and less common entities including secondary sclerosing cholangitis or AIDS cholangiopathy could be diagnosed in the proper clinical and laboratory setting. Typical abnormalities in ERCP are multifocal short strictures, which are diffusely distributed, with intervening segments of normal or dilated ducts. Liver histology may be normal because of the focal nature of the disease. The most characteristic changes are fibro-obliterative ductal lesions (22).

In the absence of an abnormal cholagiogram or AMA/ANA, the features of the liver biopsy may suggest small duct PSC or idiopathic adult ductopenia. Differential diagnosis also includes viral hepatitis, drug-induced cholestasis, benign recurrent intrahepatic cholestasis, and systemic illnesses such as lymphoma, sarcoidosis or amyloidosis.

The “clinical diagnostic scale for causality assessment in hepatotoxicity” is a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions (23).

MANAGEMENT OF CHOLESTASIS

The pathogenesis of pruritus associated with cholestasis remains poorly understood, which has precluded the development of consistently effective treatment. It has been proposed that skin accumulation of bile salts underlies the pathogenesis of cholestatic pruritus (24,25). However, bile salt concentration does not correlate with the severity of symptoms (26). It has also been suggested that hepatic accumulation of bile salt results in the rupture of cell membranes and a release of pruritogenic substances to circulation (27). On the other hand, there is increasing evidence supporting a pathogenetic role of the activation of the endogenous opioid system as the cause of cholestatic pruritus (28). Serotonin may be another mediator of pruritus, probably through central opioid modulation (29).

Mild pruritus usually responds to treatment with 4-16 g of cholestyramine. This anionic interchange resin non-specifically binds bile salts and pruritogenic susbtances in the small bowel, thus interrupting its entero-hepatic circulation (24). Major side effects of cholestyramine include constipation, fat and fat-soluble vitamin malabsorption, and an interference with the absortion of digoxine, warfarin, propranolol, thiazides and thyroxine. For these reasons, this medication should be administered 1 hour before or 4 hours after cholestyramine.

Rifampicin increases hepatic microsomal enzymes, and the sulfoxidation of bile acids, and thus facilitating their renal elimination increases the catabolism of pruritogenic sustances, while minimizing the hepatic uptake of bile acids. Two randomized, crossover, placebo-controlled studies have shown that 300-600 mg of rifampicin ameliorate pruritus in cholestasis (33,34). Another study demonstrated that this drug is better than 3 mg/kg of phenobarbitone to improve pruritus (35). Rifampicin is the drug of choice for patients with pruritus that do not respond to cholestyramine. However, side effects occur in 10%, and liver function shoud be monitored during prolonged treatment.

Phenobarbitone has been used with a single nocturnal dose of up to 100 mg/day. Its sedative effects preclude administration to patients with hepatic encephalopathy. Clinical trials with phenobarbitone are scarce and include a small number of patients. In addition, when compared to rifampicin its eficacy is lower (35). Therefore, its use in the treatment of pruritus cannot be recommended.

Treatment with 600 mg of flumecinol for three weeks has shown a slight benefit over placebo (36).

Opioid receptor antagonists such as naloxone i.v. (0.2 µg/kg/minute for 24 hours), nalmefene (60-120 mg/day), and naltrexone (50 mg/day) relieve the pruritus of cholestasis (30-32). These results indicate that oral nalmefene may be effective for pruritus relief. However, clinical trials testing such preliminary results are needed.

Small-size, open-label trials indicate that phototherapy with ultraviolet light (UV-B), high volume plasmapheresis, the molecular absorption and recirculating system (MARS), and androgens such as methyl-testosterone have shown benefits. However, these modalities cannot presently be recommended for refractory cholestatic pruritus.

Anecdotal reports have shown some benefit from the 5-HT3 antagonist ondansetron in the treatment of pruritus (37,38). Recently, a randomized controlled trial has shown a modest benefit from ondansetron over placebo (39).

Liver transplantation is indicated for cases of refractory disabling pruritus from cholestasis. In addition, it will also cure the underlying liver disease (40).

TREATMENT OF MALABSORPTION

Prolonged cholestasis may originate fat and fat-soluble vitamin malabsorption. If steatorrhea occurs, dietary fat should be restricted to 30-40 g/day. In case of malnutrition or weight loss, supplements of medium-chain triglycerides (MCT) are administered, which do not require bile salts for their absorption.

TREATMENT OF OSTEOPENIA AND FAT-SOLUBLE VITAMIN DEFICIENCY

The clinical consequences of fat-soluble vitamin deficiency are summarized in table III. In the case of vitamin A, an administration of 50.000 IU every 15 days is recommended. The levels of vitamin A should be carefully monitored to prevent hypervitaminosis A, which causes fatigue, lethargy, abdominal complaints, anorexia, skin lesions, alopecia, intracraneal hypertension, and liver toxicity. Calcium supplements (1500 mg/day) and vitamin D (266 µg of 25-hydroxy-cholecalciferol every 1-2 weeks) are useful. Careful monitoring of treatment efficacy is needed to prevent vitamin D overdosing, which may cause hypercalcemia and hypercalciuria.

Unlike the pediatric population, very few adult patients with cholestasis and low levels of vitamin E manifest neurological symptoms of vitamin E deficiency, which include peripheral neuropathy, cerebellar and retinal involvement, and ocular movement disorders. The adminitration of vitamin E, 100-200-400 IU/day is recommended for all patients with cholestasis and neurologic symptoms of uncertain etiology.

Prolonged prothrombin time from vitamin K malabsorption is rapidly corrected by administering vitamin K s.c., 10 mg/day for 3 days, and then long-term oral supplements of vitamin K, 5-10 mg/day, or 10 mg/month s.c.

TREATMENT OF OSTEOPENIA

Once a cholestatic liver disease is diagnosed, a base-line bone densitometry should be performed and then every two years. In order to preserve bone mineral density, regular exercise, moderate sunlight exposure, the ingestion of food rich in calcium, and quit smoking is recommended. Once osteoporosis is present a biphosphonate-based treatment is recommended. Cyclic administration of etidronate 400 mg/day for two weeks over a three-month period for two years prevented bone density loss in these patients (41); however, these results have not been confirmed (42). Recently, alendronate administered over a two-year period, but not etidronate, increased bone mineral density (43).

Severe osteoporosis is an indication for liver transplantation, even in the absence of hepatic failure. Although osteoporosis may worsen during the 6 months following liver transplantation, it remarkably improves thereafter (40). Transdermal oestrogens also prevent osteoporosis in post-menopausal women with cholestasis (44).

DISTURBANCE OF LIPID METABOLISM

Hypercholesterolemia above 500 mg/dl is common in PBC; however, early atherosclerosis is rare, and diet and cholestyramine are of unproved value. Considering the potential hepatotoxicity of lipid lowering agents, and the lack of clinical sequelae of hyperlipidemia in these patients, its use should be considered only in those patients with painful xanthomas. Plasmapheresis may be needed in those patients with serum cholesterol >1.000 mg/dl.

TREATMENT OF HEPATOCELLULAR FAILURE

Patients with advanced cholestatic liver disease may develop cirrhosis as well as symptoms and signs of hepatocellular failure such as ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, and bleeding from ruptured oesophageal varices. The management of these complications is similar to that of hepatic failure from other etiologies.

TREATMENT OF FATIGUE

Preliminary results suggest that treatment with ondansetron (4 mg/8 h p.o.) ameliorates fatigue in these patients (45). This improvement may be related to a central effect on serotoninergic transmission.

SPECIFIC TREATMENT OF CHOLESTATIC SYNDROMES

In the case of primary biliary cirrhosis (PBC), different treatments such as steroids, azhathioprine, methotrexate, cyclosporin, clorambucil, mycophenolate, D-penicilamine, and bezafibrate have been tested. However, the small size of trials and their lack of consistent clinical benefit have precluded routine use of these agents in the treatment of PBC. Ursodeoxycholic acid (UDCA) 8-15 mg/kg/day for 3 months-5 years has been used in 16 randomized clinical trials; in all, 1422 patients were included. Results have been summarized in a recent meta-analysis and a Cochrane hepatobiliary systematic review (46,47). No benefit on mortality (OR: 0.94; 95% CI (0.60-1.48)), need for liver transplantation (OR 0.83; 95% CI (0.52-1.32)), or both (OR: 0.9; 95% CI (0.65-1.26)) could be found. There was no benefit for fatigue, serum albumin, or prothrombin either. However, ascites, jaundice, serum bilirubin, and transaminases improved. An analysis of patients with more advanced disease or more prolonged treatment did not change results. Several studies testing higher doses of UDCA for PBC are ongoing. This drug may exert a positive effect on histology and on some clinical and laboratory parameters (47), and exhibit a remarkable absence of important side effects. For these reasons UDCA is the most widely used drug in the treatment of PBC.

Liver transplantation is indicated for those patients with PBC who have serum bilirubin >6 mg/dl, signs of portal hypertension (ascites, encephalopathy, ruptured oesophageal varices), or when a hepatocellular carcinoma develops (40).

The specific treatment of primary sclerosing cholangitis (PSC) includes the management of local complications such as biliary sepsis (antibiotics ± endoscopic treatment), and the management of biliary stones. Ursodeoxycolic acid 10-15 mg/kg/day improves the biochemistry and histology in these patients; however, no benefit on survival has been demonstrated (47).

Liver transplantation is indicated for PSC when recurrent episodes of bacterial cholangitis, persistent jaun-dice, complications of cirrhosis, or refractory pruritus develop (40).

Several trials have shown that UDCA improves biochemistry, although a benefit on survival is yet unproved. Some patients showing cholestatic lesions overlaping with autoimmune hepatitis obtain biochemical improvement with steroids alone or with azathioprine. Thus far, there are no markers allowing to distinguish between responders to UDCA and responders to immunosuppressants, and therefore therapeutic options should be based on biopsy findings. In end-stage liver disease hepatic transplantation should be considered (49-53). Although UDCA may improve the biochemistry of patients with adult idiopathic ductopenia, current data do not suffice to recommend it (54). In some cholestatic liver diseases such as GVHD and liver rejection, immunosuppressants should be instituted as early as possible. In Hodgkin’s disease, chemotherapy is the basis of treatment whereas in drug-induced hepatic cholestasis the withdrawal of the offending drug is mandatory (55).

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