Hepatocellular carcinoma in long-term oral contraceptive use

Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies in certain parts of the world, particularly in Africa and Asia, but it is less commonly encountered in the United States. It is closely associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and almost always develops in a cirrhotic liver. In non-cirrhotic livers, HCC is found in about 20% of asymptomatic carriers of HBV and rarely in patients taking androgenic-anabolic or oral contraceptive (OC) steroids. We report four patients, who developed HCC after prolonged use of OC steroids. Whether OC steroids act as mutagen or co-carcinogen in hepatocarcinogenesis is not clear. To exclude latent HCV and HBV infections which may occur in the absence of their serological markers, we employed polymerase chain reaction for the detection of HBV and HCV sequences in the tumor and non-tumorous liver tissue. Viral sequences of HBV and HCV were undetectable in all four cases. These findings suggest OC use as the only known risk factor in these cases and, therefore, strengthen its possible role in hepatocar-cinogenesis.     

Morphological aspects of manganese-bilirubin induced cholestasis

ABSTRACT— Small doses of manganese or bilirubin administered alone to rats produce no morphologic alterations in the hepatocytes. However, combination of both treatments produced a rapid and severe decrease in bile flow that was paralleled by the appearance and aggravation of the cholestatic lesion: bile canaliculi progressively lost their microvilli; vacuolization occurred in the pericanalicular area and subsequently in the cytoplasm. When bile flow returned to normal, or when cholestasis was prevented by an injection of sulfobromophthalein or a pretreatment with phalloidin, no cholestatic signs were observed. A close correlation appears to exist between the presence of morphologic alterations and the decrease of bile flow in manganese-bilirubin cholestasis.     

妊娠期肝内胆汁淤积症

妊娠期肝内胆汁淤积症（ICP）为一种妊娠期特有的疾病,其病因不详。该病首次报道于19世纪80年代,于20世纪60年代得到详细报道,属高危妊娠之列。ICP最大的危害是发生胎儿窘迫,常使胎儿突然胎死宫内,并增加母体产后出血的风险。临床主要症状为瘙痒。临床上对ICP的处理存在两种过激的倾向,因此对ICP的诊断需规范化,需排除其他相关性疾病。建议诊断时进行分度,以便合理制定临床治疗方案,避免处理上的盲目性     

Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11

BACKGROUND & AIMS: Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are hereditary liver disorders; PFIC is characterized by severe progressive liver disease whereas BRIC patients have intermittent attacks of cholestasis without permanent liver damage. Mutations in ATP8B1 are present in PFIC type 1 and in a subset of BRIC patients. We hypothesized that a genetically distinct form of BRIC is associated with mutations in ABCB11. This gene encodes the bile salt export pump (BSEP) and is mutated in PFIC type 2. METHODS: Patients from 20 families were included; all had a normal ATP8B1 sequence. Sequencing of all 27 coding exons including the splice junctions of ABCB11 revealed 8 distinct mutations in 11 patients from 8 different families: one homozygous missense mutation (E297G) previously described in PFIC2 patients, 6 novel missense mutations, and one putative splice site mutation. RESULTS: In 12 families, no mutations in ATB8B1 or ABCB11 were detected. Pancreatitis is a known extrahepatic symptom in BRIC caused by ATP8B1 mutations, but was not present in BRIC patients with mutations in ABCB11. In contrast, cholelithiasis was observed in 7 of 11 BRIC patients with mutations in ABCB11, but has not been described in ATP8B1-affected BRIC patients. CONCLUSIONS: Mutations in ABCB11 are associated with BRIC, and consistent with the genetic classification of PFIC into 2 subtypes, we propose that this disorder be named BRIC type 2.     

Acute cholestatic hepatitis induced by bupropion prescribed as pharmacological support to stop smoking. A case report

We report the first case of acute cholestatic hepatitis induced by bupropion. This antidepressant was taken by a 49-year-old female as adjuvant treatment to stop smoking. After 20 days of bupropion, the patient presented a symptomatology characterized by asthenia, nausea and scleral icterus and biochemical analyses showed a dramatic increase in direct bilirubin (up to 28 mg/dl) and transaminases (up to 68-fold normal limits). Antinuclear antibodies were positive (title = 1:80; speckled pattern). Biochemical analyses and antinuclear antibodies were normal two years earlier. The histology showed a pattern of acute hepatitis with involvement of bile ducts and with features of centrolobular cholestasis. Treatment with methylprednisolone was commenced and continued for 20 days. Liver enzymes and bilirubin returned to normal within two months of withdrawal of bupropion and remained normal during the 4-month follow-up. Antinuclear antibodies also became negative. Other causes of liver damage were excluded. Considering the clinical diagnostic scale for hepatotoxic adverse drug reaction, our patient showed a score compatible with the final diagnosis of bupropion-related cholestatic hepatitis.     

Expanding etiology of progressive familial intrahepatic cholestasis

BACKGROUND Progressive familial intrahepatic cholestasis(PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.AIM To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management.METHODS We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles.We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format.RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1(ATP8 B1), BSEP(ABCB11), and MDR3(ABCB4) transporter deficiencies, as well as more recently described gene mutations--TJP2(TJP2), FXR(NR1 H4), MYO5 B(MYO5 B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.     

Smoking,the oral contraceptive pill,and Crohn's disease

Both cigarette smoking and the oral contraceptive pill have been implicated as aggravating factors in Crohn's disease. Based upon the recent demonstration of multifocal gastrointestinal infarction in Crohn's disease, a possible pathogenic mechanism for this condition, we propose how smoking and the oral contraceptive pill may potentiate a tendency for focal thrombosis and hence exacerbate the activity of Crohn's disease.     

Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder that usually develops in the third trimester of pregnancy and persists until delivery. The cause of ICP remains elusive, but there is evidence that mutations in the canalicular ABC transporter phospholipid flippase (MDR3) and in the bile salt export pump (BSEP) can predispose for the development of ICP. MDR3 and BSEP were investigated by gene sequencing and immunofluorescence microscopy in a patient with severe ICP of early onset. ICP was diagnosed in a patient in the first trimester of pregnancy with severe pruritus, elevated levels of bile salts, and 48-fold elevation of transaminase levels. A liver biopsy specimen showed diminished canalicular expression of the bile salt export pump BSEP, while the expression and localization of the phospholipid flippase MDR3 was normal. Gene sequencing revealed a homozygous MDR3 gene mutation (S320F). The patient was also homozygous for the common BSEP polymorphism V444A. Treatment with ursodeoxycholate normalized transaminase levels but could not prevent further elevation of bile salt levels and preterm delivery. The combined homozygous alterations of the canalicular transporters may explain the early onset and severity of ICP in this patient. The common BSEP polymorphism V444A accounts for the reduced canalicular BSEP expression. Reduced bile salt secretion through BSEP may explain the persistence of elevated bile salt levels and incomplete efficacy of ursodeoxycholate treatment.     

Atypical causes of cholestasis

Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.     

Association between duration of oral contraceptive use and risk of hypertension: A meta‐analysis

A meta‐analysis was conducted to evaluate the association between duration of oral contraceptive use and risk of hypertension. Relevant studies published in English or Chinese were identified by a search of PubMed, Web of Science, Wanfang Database, and China National Knowledge Infrastructure to January 2017. Seventeen articles containing 24 studies with 270,284 participants were included in this meta‐analysis. The pooled relative risk of hypertension for the highest vs lowest category of oral contraceptive duration was 1.47 (95% confidence interval, 1.25–1.73), and excluding three studies with a relative risk >3.0 yielded a pooled relative risk of 1.26 (95% confidence interval, 1.11–1.44). A linear dose‐response relationship was found (P_nonlinearity=0.69) and the risk of hypertension increased by 13% (relative risk, 1.13; 95% confidence interval, 1.03–1.25) for every 5‐year increment in oral contraceptive use. The duration of oral contraceptive use was positively associated with the risk of hypertension in this meta‐analysis.     

进行性家族性肝内胆汁淤积

进行性家族性肝内胆汁淤积(PFIC)是一组常染色体隐性遗传肝细胞源性儿童胆汁淤积症。根据病因可以分为3型：1型源于ATP8B1基因的突变,2型源于ABCB11基因的突变,3型源于MDR3基因的突变。临床以有胆汁淤积以及严重的皮肤瘙痒为特征。治疗方法包括药物治疗、外科部分胆道外分流术和肝移植三种方法。     

中医体质分型与妊娠期肝内胆汁淤积症的关系

[目的]结合中医体质学说,探讨妊娠期肝内胆汁淤积（ICP）的孕妇体质类型的分布,以及体质与ICP病情严重程度的关系.[方法]以2011年5月～2013年5月在我院住院的34例ICP的孕产妇为观察组,30例正常孕妇为对照组,进行中医体质和ICP病情评估,整理数据并进行统计分析.[结果]观察组偏颇体质孕妇占73.53％（25/34）,显著高于对照组的43.33％（13/30）,差异有统计学意义（x2=6.025,P＜0.05）.观察组25例偏颇体质患者中以湿热质、痰湿质和血瘀质为最多见类型,分别占26.47％,26.47％和20.59％.其中血瘀质患者ICP病情严重程度明显重于湿热质患者,差异有统计学意义（x2 =6.349,P＜0.05）,也重于痰湿质患者,但差异无统计学意义（x2=3.654,P＞0.05）.[结论]偏颇体质孕妇较平和体质孕妇易发生ICP,尤其是湿热质、痰湿质和血瘀质体质孕妇,而且以血瘀质型孕妇ICP病情更重.     

Amoxycillin/clavulanic acid (augmentin)-induced intrahepatic cholestasis

Summary A 75-year-old man developed a biopsy-proven, drug-induced intrahepatic cholestasis after use of amoxycillin trihydrate combined with the -lactam inhibitor potassium clavulanate (Augmentin). Cholestatic liver injury is an uncommonly recognized, probably immunologically based adverse reaction to therapy with penicillin and its derivatives.     

黄疸型婴儿肝炎预后与血清谷氨酰转肽酶水平变化的关系

目的研究血清谷氨酰转肽酶（GGT）水平与黄疸型婴儿肝炎预后的关系。方法回顾性分析38例除外先天性胆道闭锁和其他先天性异常后的黄疸型婴儿肝炎的临床资料,以死亡、肝移植或等待肝移植、1岁后仍持续或反复黄疸为预后不良指标,按最初GGT的高低分为≤50U／L和〉50U／L组并分析两组患者的预后有无差别。结果最初的GGT≤50U／L组6例中5例预后不良;〉50U／L组32例中3例预后不良,差别有统计学意义（P=0．001）。动态分析发现,8例预后不良患儿中5例GGT始终在正常水平,与胆红素和转氨酶等指标波动无关;3例GGT在开始时升高,随病情进展,反而降为正常。预后良好患儿,随黄疸消退,GGT渐达高峰然后恢复正常。结论在黄疸型婴儿肝炎中,GGT不升或随黄疸加深或持续,GGT反而降为正常,是预后不良的指标;病程中黄疸波动,而GGT始终正常者,需考虑有进行性家族性肝内胆汁淤积可能。     

Treatment of pruritus with Prometheus dialysis and absorption system in a patient with benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disorder characterized by recurrent episodes of jaundice and itching. Episodes of cholestasis last variously from 1 week to several months, may start at any age and usually resolve spontaneously. No effective treatment has been found as yet. We report a case of genetically proven BRIC in a male patient who developed three episodes of pruritus and jaundice at the age of 14, 16 and 19 years. During the third episode, he did not respond to pharmacological medical therapy, and fractionated plasma separation and absorption (FPSA, Prometheus) was performed to manage intractable pruritus. The treatment immediately alleviated pruritus, lowered serum bilirubin concentration and induced sustained remission in the 5‐year follow up. FPSA seems to be a safe and effective way of treatment for BRIC in patients with severe pruritus and prolonged jaundice.     

Portal vein thrombosis associated with prolonged ingestion of oral contraceptive steroids

The case is described of a 38 year old woman who developed severe right upper quadrant abdominal pain that was associated with partial portal vein occlusion, as confirmed by flow Doppler ultrasonography and dynamic contrast computed tomography. The patient was a cigarette smoker and had taken combined oestrogen/progestagen oral contraceptive steroids (OCS) continuously for 24 years. There were no other risk factors for portal vein thrombosis or for thromboembolic disease. Following anticoagulant therapy and discontinuation of OCS complete recovery occurred. The case is reported to draw attention to portal vein thrombosis as an extremely rare complication of OCS.