A case of severe cholestatic jaundice with hyperthyroidism successfully treated with methimazole

Liver dysfunction is a common complication observed in patients with hyperthyroidism, however the dysfunction is always mild and obvious jaundice is rarely observed. We present the case of a 43-year-old man who suffered from hyperthyroidism complicated by severe jaundice. The jaundice likely occurred as a secondary consequence of cholestasis due to hyperthyroidism, since other causes such as drug-induced or autoimmune liver dysfunction were ruled out. Treatment with methimazole improved severe cholestatic jaundice in parallel with normalization of thyroid function. The mechanism of cholestasis as a secondary complication of hyperthyroidism has not been uncovered and there is no specific biochemical marker for cholestasis due to this hormonal disease at present. This case serves as a reminder that severe jaundice can be a manifestation of simple hyperthyroidism, and that administration of antithyroid drugs is an effective treatment for severe cholestatic jaundice in such cases.     

Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis

We report the case of a middle-age patient presenting with severe progressive protoporphyric cholestasis. To halt further progression of liver disease, medical treatment was given aimed at different mechanisms possibly causing cholestasis in erythropoietic protoporphyria. Within eighty days, liver biochemistry completely normalized and liver histology markedly improved. Bone marrow transplantation was performed to prevent relapse of cholestatic liver disease by correcting the main site of protoporphyrin overproduction. Thirty-three months after cholestatic presentation and ten months after bone marrow transplantation, liver and porphyrin biochemistry remains normal. The patient is in excellent condition and photosensitivity is absent. The theoretical role of each treatment used to successfully reverse cholestasis and the role of bone marrow transplantation in erythropoietic protoporphyria are discussed. Medical treatment can resolve hepatic abnormalities in protoporphyric cholestasis. Bone marrow transplantation achieves phenotypic reversal and may offer protection from future protoporphyric liver disease.     

Recurrent intrahepatic cholestasis of pregnancy and chain-like choledocholithiasis in a female patient with stop codon in the ABDC4-gene of the hepatobiliary phospholipid transporter

We report the case of a 40-years-old female patient with recurrent cholestatic liver disease who presented twice with severe intrahepatic cholestasis of pregnancy and pronounced choledocholithiasis between pregnancies. Bile duct stones were removed endoscopically and a laparoscopic cholecystectomy was performed after the second pregnancy. Liver histology revealed intrahepatic cholestasis with portal inflammation and fibrosis, resembling progressive familial intrahepatic cholestasis (PFIC). Molecular genetic studies identified the heterozygous mutation c.957C > T in the ABCB4 gene encoding the hepatobiliary phospholipid transporter. This is the first report of this mutation that introduces a stop codon in an index patient with intrahepatic cholestasis of pregnancy and multiple bile duct stones. In addition, we detected the ABCB11 polymorphism V 444A, which is associated with a decreased expression of the bile salt export pump. Whereas homozygous carriers of the ABCB4 mutation develop PFIC type 3, the heterozygous ABC transporter mutations represent genetic risk factors for cholelithiasis and recurrent cholestatic hepatitis upon challenge with oral contraceptives or during pregnancy. Of note, the patient presented with normal serum gamma-glutamyltranspeptidase activities during pregnancy-associated cholestatic episodes but normal liver enzymes after delivery, whereas choledocholithiasis was associated with high gamma-glutamyl transpeptidase levels. It is unknown whether ursodeoxycholic acid prevents cholestasis or gallstones in patients with ABCB4 deficiency.     

Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of γ-glutamyl transpeptidase

Objective: Rifampicin is an effective drug against pruritus in intrahepatic cholestasis. However, there is no specific hepatic disease in which its use could cause undoubtedly biochemical improvement. The aim of this study was to describe patients with complete remission of cholestatic symptoms after rifampicin therapy.
Methods: We reported three female patients with intrahepatic cholestasis with no evidence of viral, metabolic, or autoimmune liver diseases. Total bilirubin levels ranged from 13.2 to 27.2 mg/dl (before the first treatment with rifampicin), and in all of them γ-glutamyl transpeptidase values were within the normal range or slightly increased. Rifampicin therapy was administered orally, without any concomitant drug, with an effective dosage of 5–17 mg/kg/day.
Results: In all patients, pruritus ceased completely and bilirubin returned to normal values. The symptoms recurred after rifampicin withdrawal on, at least, three occasions in each patient, and these symptoms were always eliminated after its reintroduction. The patients had a total of 16 cholestatic episodes during a follow-up of 8 yr, with a complete clinical recovery in all of them. Undergoing therapy with a suitable dosage of rifampicin, none of the patients had a cholestatic crisis even during a period for as long as 12 months. The diagnosis of two patients was consistent with benign recurrent intrahepatic cholestasis, and it was not well defined in the remaining.
Conclusion: Rifampicin may induce clinical remission, and perhaps prevent clinical relapses of intrahepatic cholestasis with normal or slightly increased levels of γ-glutamyl transpeptidase.     

Cholestatic jaundice associated with the use of metformin

We report a patient who developed cholestatic jaundice shortly after initiation of treatment with metformin hydrochloride. Ultrasound of the liver and abdominal CT were normal. An ERCP showed normal biliary anatomy. A percutaneous liver biopsy was obtained showing marked cholestasis, with portal edema, ductular proliferation, and acute inflammation. Metformin hydrochloride was discontinued, and the patient's jaundice resolved slowly over a period of several months. Given the onset of his jaundice 2 wk after the initiation of metformin, we believe that this case represents an example of metformin-associated hepatotoxicity, the first such case reported.     

A case report: nasobiliary drainage inducing remission in benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis is a rare hereditary disorder characterized by recurrent episodes of cholestasis and pruritus without anatomical obstruction. Generally, medical therapy is not effective in benign recurrent intrahepatic cholestasis. Here, we report the case of a young male patient with benign recurrent intrahepatic cholestasis who presented with cholestatic jaundice and pruritus, refractory to standard therapies. He improved on treatment with temporary endoscopic nasobiliary drainage. We propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. A 36-year-old male patient admitted to our outpatient clinic with the complaint of pruritus. His anamnesis revealed that he experienced the same symptoms and signs in 2006. He was hospitalized in a hepatology clinic and was thoroughly examined. Liver biopsy was performed, and he was finally diagnosed as having benign recurrent intrahepatic cholestasis. Medical therapy options all proved to be ineffective and we were able to achieve remission in this patient only with the help of nasobiliary drainage. For this patient, we tried nasobiliary drainage in addition to the standard medical therapies. He improved on nasobiliary drainage. In conclusion, we propose that temporary endoscopic biliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. We hope that this case report contributes to the topic, since only a few nasobiliary drainage case experiences have been reported to date.     

Pruritus in chronic cholestatic liver disease

Pruritus is a troublesome complication in patients with cholestatic liver disease. Several links to its pathogenesis have been proposed, including the role of bile acids, endogenous opioid and serotonins, and lysophosphatidic acid. The management of pruritus in cholestasis is challenging. Medical treatment of the underlying cholestatic condition may provide benefit. Extracorporeal albumin dialysis can be pursued for those who have a poor quality of life and failed the various therapeutic interventions, while awaiting liver transplantation. Experimental interventions, and the management of pruritus in certain conditions such as intrahepatic cholestasis of pregnancy and benign recurrent intrahepatic cholestasis, are also briefly reviewed.     

Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by episodic cholestasis and pruritus without anatomical obstruction. Effective medical treatment is not available. We report complete and long-lasting disappearance of pruritus and normalization of serum bile salt concentrations in cholestatic BRIC patients within 24 hours after endoscopic nasobiliary drainage (NBD). Relative amounts of phospholipids and bile salts in bile collected during NBD appeared to be normal, but phospholipids other than phosphatidylcholine (especially sphingomyelin) were increased. In conclusion, we propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic BRIC patients.     

Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism

Ursodeoxycholic acid was administered to a patient with benign recurrent intrahepatic cholestasis to prevent cholestatic episodes. A detailed study of bile acid metabolism in this patient was carried out in the anicteric and icteric phases before and after ursodeoxycholic acid (750 mg/day) administration. Urinary, biliary and serum bile acids were measured by gas chromatography-mass spectrometry and by high-performance liquid chromatography techniques. During the anicteric phase the daily urinary excretion and serum concentrations of bile acids were within normal ranges, indicating normal hepatic uptake and secretion of bile acids during the cholestasis-free period. Only slight qualitative differences from normal individuals were observed; the relative proportions of deoxycholic acid in the bile and serum were higher, and 12-oxo-lithocholic acid was the predominant urinary bile acid. During the icteric phase a marked increase in the urinary excretion of primary bile acids and C-1, C-2, C-4 and C-6 hydroxylated metabolites was found. Serum bile acid concentrations increased before the rise in bilirubin, suggesting an acute disturbance in bile acid transport at the onset of the cholestatic attack. After ursodeoxycholic acid administration in the anicteric phase, bile became enriched with the exogenous bile acid, but little qualitative change was found in the other metabolites present in the urine, serum or bile during the anicteric or icteric phases. Prolonged administration of ursodeoxycholic acid failed to prevent recurrence of a cholestatic episode, suggesting that in benign recurrent intrahepatic cholestasis, oral ursodeoxycholic acid may be of little benefit in the treatment or prevention of cholestasis despite marked enrichment of the bile acid pool with this hydrophilic bile acid.     

Endogenous opioids modulate hepatocyte apoptosis in a rat model of chronic cholestasis: the role of oxidative stress.

AIMS/BACKGROUND: There are increasing number of evidences indicating the contribution of endogenous opioids in the pathophysiology of cholestatic liver disease. The aim of the present study was to determine the role of the endogenous-opioid system in the modulation of hepatocytes apoptosis and liver oxidant/anti-oxidant balance during chronic cholestasis in rats. METHODS: We induced cholestasis in rats by bile duct ligation (BDL). Naltrexone, an opioid antagonist, was administered at different doses (2.5, 5, 10, 20 and 40 mg/kg/day) to cholestatic animals for 5 weeks. RESULTS: Naltrexone prevented the cholestasis-induced decrease of hepatic glutathione levels at higher doses (20 and 40 mg/kg/day). In the next phase of the study, we evaluated the effects of 20 mg/kg/day naltrexone treatment on hepatic damage indices and liver oxidant/anti-oxidant balance in 5-week BDL rats. There was a marked increase in the number of apoptotic hepatocytes as well as serum liver enzymes and hepatic lipid peroxidation levels in cholestatic rats compared with sham-operated animals 5 weeks after the operation. Liver anti-oxidant enzyme activities were significantly reduced in cholestatic rats compared with controls. Chronic treatment with naltrexone significantly improved all the aforementioned indices in comparison with saline-treated cholestatic rats. CONCLUSION: Our findings demonstrate that the administration of opioid antagonist is protective against hepatic damage in a rat model of chronic cholestasis. We suggest that increased levels of endogenous opioids contribute to hepatocytes apoptosis in cholestasis, possibly through downregulation of liver anti-oxidant defense.     

Expression of platelet-derived growth factor in newly formed cholangiocytes during experimental biliary fibrosis in rats.

BACKGROUND/AIMS: Chronic cholestasis stimulates a fibroductular reaction which may progress to secondary biliary fibrosis and cirrhosis. Since platelet-derived growth factor has been indicated as a major fibrogenic factor in chronic liver disease, we analyzed its expression and that of its receptor beta subunit in a rat model of chronic cholestasis. METHODS: Liver tissue samples collected at 7, 10, 21, and 28 days after induction of cholestasis obtained by bile duct ligation, were analyzed by immunohistochemistry, in situ hybridization and RNase protection assay for the expression of platelet-derived growth factor (PDGF)-B chain and receptor beta subunit. Furthermore, the expression of PDGF-B chain mRNA was analyzed in highly purified cholangiocytes from normal and cholestatic rat liver. RESULTS: In cholestatic liver, platelet-derived growth factor-BB and B chain mRNA expression increased up to 4 weeks in epithelial cells of proliferating bile ducts, and periductular mesenchymal cells. The increased expression of PDGF-B chain mRNA was confirmed in highly purified cholangiocytes obtained from normal and cholestatic rat liver. The expression of the receptor beta subunit progressively increased after induction of cholestasis and was mainly localized to desmin-positive periductular hepatic stellate cells. CONCLUSIONS: These data suggest that platelet-derived growth factor-B chain can be synthesized by cholangiocytes during chronic cholestasis. The presence of its receptor on periductular hepatic stellate cells raises the possibility that, in this experimental setting, this cytokine might contribute to fibrogenesis in vivo.     

Cholestasis diagnostics. Experiences with the percutaneous transhepatic cholangiography (PTC) using the Chiba needle (author's transl)

We were successfull in doing a percutaneous transhepatic cholangiography (PTC) using the Chiba needle in 29 out of our 32 first cases including 19 out of 20 icteric and 10 out of 12 unicteric patients. Already when getting familiarized with the procedure the PTC seems to be superior as compared to the endoscopic retrograde cholangiography (ERC) in regard to results, risks, inconvenience to the patient, costs and technical skill. In this way the cholestasis diagnostics could be improved also in smaller hospitals missing the personnel and instrumental requirements to do the ERC procedure.     

Cholestatic jaundice induced by D-penicillamine and oral steroid contraceptive in progressive systemic sclerosis (author's transl)

A 25-year-old woman with progressive systemic sclerosis was treated with D-penicillamine. (DPA) 30 days after starting therapy cholestatic jaundice was observed. Moreover, for two years she has taken the pill. Both drugs were discontinued, the jaundice disappeared and the laboratory findings of liver became normal. A rechallenge of D-penicillamine after 9 months induced no reaction. An underlying chronic liver disease before cholestasis could be excluded by liver biopsy. Allergic cutantests and lymphocyte transformation test with D-penicillamine and penicillin gave normal results. The frequency of cholestatic jaundice caused by DPA-therapy is discussed and the possible pathomechanism analyzed.     

Benign recurring intrahepatic cholestasis--a case report

The diagnosis of benign recurrent intrahepatic cholestasis was made in a 40 year old female. Seven episodes of jaundice persisting up to 6 months in lengths lead to 3 laparotomies, numerous peritoneoscopies and needle biopsies of the liver. Elevation of conjugated serum bilirubin and alkaline phosphatase levels and histopathological confirmation of intrahepatic cholestasis without cholangitis were the main characteristics during the episodes of cholestatic jaundice. However, hepatic histology and liver function were normal in remission periods. Drug induced cholestasis was ruled out by careful history. A sister also suffered from 4 episodes of intrahepatic cholestasis. The etiology of the disease is probably of a genetic origin. The pathogenesis remains unclear. There is no specific treatment to prevent or shorten the occurrence of cholestatic episodes. The patients are advised to avoid pregnancy and oral contraceptives, since both will induce icteric phases.     

Steroids for the treatment of methimazole-induced severe cholestatic jaundice in a 74-year-old woman with type 2 diabetes

Methimazole is a widely used antithyroid agent. Although methimazole is generally well tolerated, rare but severe cholestatic jaundice may occur. We described a 74-year-old woman who had a 10-year history of type 2 diabetes had developed severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (10 mg tid) for the treatment of hyperthyroidism. Clinical investigations revealed no evidence of any mechanical obstruction in the common bile duct or other obvious causes of hepatic injury, and the diagnosis methimazole-induced cholestasis was made on the basis of the temporal relationship between initiation of methimazole and onset of cholestasis. Methimazole was hence discontinued. However, the patient experienced a progressive worsening in cholestasis after receiving 2 weeks of ursodeoxycholic acid (UDCA) therapy. Prednisone therapy was then attempted. Liver function tests eventually improved with combination of glucocorticoids and ursodeoxycholic acid therapy. This case clearly showed that glucocorticoids could be a possible additional way of treatment for some cases of drug-induced cholestatic jaundice even in diabetic patients.     

Cholestatic jaundice as a paraneoplastic manifestation of prostate adenocarcinoma.

Malignancies may cause cholestatic jaundice through well-recognized mechanisms (e.g., bile duct obstruction or widespread hepatic infiltration). Paraneoplastic syndromes associated with malignancy, particularly with renal cell carcinoma (Stauffer's syndrome) and malignant lymphoproliferative diseases, can induce a reversible form of cholestasis through an unclear pathogenetic mechanism. Prostate cancer presenting initially with cholestatic jaundice without any obvious cause (i.e., obstruction or infiltration) has been reported in 2 cases in the medical literature. We report a patient who presented with pruritus and cholestatic jaundice. During the diagnostic work-up, prostate cancer was diagnosed. Conjugated bilirubin and alkaline phosphatase levels were increased markedly with modest increases of gamma-glutamyltranspeptidase and transaminase levels. The results of appropriate investigations performed during the patient's hospitalizations indicated no evidence of hepatic metastases or extrahepatic biliary obstruction. After treatment with flutamide and leuprolide, the patient's symptoms and the laboratory abnormalities reversed rapidly. We regard the cholestatic jaundice of this patient as part of a paraneoplastic syndrome; the cause of cholestasis remains an enigma. Patients with unexplained cholestasis should be investigated for malignancies, including prostate cancer.     

Obstructive jaundice associated Burkitt's lymphoma mimicking pancreatic carcinoma

The primary compromise of the pancreas in lymphomas is uncommon. However, in advanced stages of Non-Hodgkin's lymphomas (LNH) the secondary invasion of the pancreas is observed more frequently. Jaundice due to extrahepatic cholestasis as a presentation form is extremely rare, with only few cases described in the literature. The aim is to present a case of an obstructive jaundice as an expression of Burkitt's lymphoma probably due to a diffuse pancreatic infiltration in an adult without immunodeficiency with a rapid response of cholestasis to low dose of hydrocortisone. Skin tumor simultaneously present with jaundice allowed the histologic diagnosis with skin biopsies. After a unique dose of 100 mg hydrocortisone, jaundice improved and cholestatic enzymes decreased, pancreas became smaller and common bile duct diameter became normal at ultrasound and CT scan, also skin tumors turn pale and diminished in size. There are isolated reports of Burkitt's lymphoma cases with associated obstructive jaundice due to pancreatic infiltration or by compression by lymph nodes of the bile ducts, many of them are pediatric cases or immunodepressed HIV patients. In the case presented, surgical resection of the pancreatic infiltration and biliary drainage, either surgical or endoscopic during the same procedure was not necessary for the histopathologic diagnosis of the illness like is described in the literature. The diagnosis was suspected by the rapid decrease of cholestatic features after a single dose of hydrocortisone and the histology was easy done by a skin biopsy. We think the interest in this case is the quick response to low doses of corticoids, which avoided the necessity of surgical procedure for the diagnosis of the biliary tree obstruction, allowing a quick implementation of the specific chemotherapeutic treatment of the lymphoma without any surgical or endoscopic procedures to heal the jaundice.     

Benign recurrent intrahepatic cholestasis: late initial diagnosis in adulthood

Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive or sporadic disorder, characterized by recurrent episodes of intense pruritus and jaundice that resolve spontaneously without leaving considerable liver damage. The attacks can start at any age, but the first attack is usually seen before the second decade of life. We report the case of a young adult male patient with BRIC who presented with recurrent cholestatic jaundice and pruritus with negative work up for all possible etiologies and a liver biopsy consistent with intrahepatic cholestasis. He improved on treatment with rifampicin and has not suffered another attack on follow up. Although in adulthood, BRIC diagnosis should be kept in mind in patients with recurrent cholestatic attacks with symptom free intervals after main bile duct obstruction and other congenital or acquired causes of intrahepatic cholestasis excluded.     

Hyperbilirubinemia and cholestatic liver injury in hepatitis C-infected liver transplant recipients

OBJECTIVE: A cholestatic pattern of liver injury has been observed in liver transplant recipients with rapidly progressive hepatitis C. We assessed the frequency and causes of cholestasis in hepatitis C-infected liver transplant patients, and evaluated the clinical and pathological course of those with cholestatic hepatitis C. METHODS: Sixty-nine sequential liver transplant recipients who had detectable hepatitis C viremia were studied retrospectively. Records and diagnostic tests were examined from patients who developed hyperbilirubinemia. RESULTS: Hyperbilirubinemia occurred in 33 of 69 (48%) hepatitis C-infected liver transplant patients. A thorough evaluation including review of clinical and laboratory data, ultrasound with Doppler, cholangiogram, and liver biopsy identified causes of hyperbilirubinemia other than hepatitis C in 26 of 33 patients. Seven patients developed cholestatic hepatitis C characterized by histological features of recurrent hepatitis C and cholestatic liver injury with ballooning of centrilobular hepatocytes, bile ductular proliferation, and canalicular cholestasis, in the absence of other causes of cholestasis. Five progressed rapidly to bridging fibrosis and two died of complications related to liver failure. Four patients with cholestatic hepatitis C showed extended survival after the onset of hyperbilirubinemia. CONCLUSIONS: 1) Hepatitis C is a relatively infrequent cause of cholestasis in liver transplant recipients. 2) The diagnosis of cholestatic hepatitis C requires a multimodality approach to exclude other causes of cholestasis. 3) Cholestatic hepatitis C ranges in severity and is not always associated with rapid development of graft failure, although significant histological abnormalities are frequent.     

Cholestatic liver diseases: slow progress in understanding and treating slowly progressive disorders

BACKGROUND: Cholestatic liver diseases are characterized by failure of normal amounts of physiological bile to reach the gastrointestinal tract. Any interference with normal bile flow from the canalicular membrane of the hepatocyte to the distal common bile duct may result in cholestasis. METHODS: Literature review. RESULTS: In primary biliary cirrhosis (PBC), the small intrahepatic bile ducts are destructed, resulting in obstruction of intrahepatic bile flow, whereas extrahepatic and/or intrahepatic biliary strictures block the passage of bile towards the intestine in primary sclerosing cholangitis (PSC). In contrast, the biliary tree is morphologically unaffected in less common cholestatic liver diseases as benign recurrent intrahepatic cholestasis (BRIC) and progressive familiar intrahepatic cholestasis (PFIC1-4). Genetic defects in hepatic canalicular transport mechanisms and bile salt synthesis deficiencies seem to underlie these types of cholestatic disorders. CONCLUSION: Recent advances in understanding and treatment of cholestatic liver diseases may help in better diagnosing and treating the various conditions characterized by cholestasis.