When was cirrhosis first discovered

Presence of nodules and fibrous septa with effacement of the lobular architecture. The nodules are of two types: Dissection type and Hyperplastic Regenerative type. Notice presence of portal vein, portal artery but no bile duct. This case was interpreted as "vanishing duct syndrome". Are, with nodules, the other characteristic component of cirrhosis and they are visible even with the naked eye.

They have been termed "fibro-vascular membranes" which provide a diversion of the blood flow through an alternative route along these fibrous septa instead of through the acinar sinusoids, thus affecting the physiology of the hepatocytes Rappaport AM et al. A, The fibrous septa are basically granulation tissue more or less active according to the degree of edema, capillarization, inflammatory cell infiltration and fibrosis.

They reflect the activity of the cirrhotic process. The evolution can be assessed on degree of fibrosis and nodule formation. The following stages can be identified with some approximation even on a needle biopsy specimen:.

There are distended efferent vessels around the septum. Diagnosis made via contrast cholangiography, can be supported clinically by positive antimitochondrial antibody primary biliary cirrhosis or antineutrophil cytoplasmic antibody primary sclerosing cholangitis in high titers. Information from references 14 , 15 , 18 , and Although various radiographic studies may suggest the presence of cirrhosis, no test is considered a diagnostic standard.

Abdominal ultrasonography with Doppler is a noninvasive, widely available modality that provides valuable information regarding the gross appearance of the liver and blood flow in the portal and hepatic veins in patients suspected to have cirrhosis.

Ultrasonography should be the first radiographic study performed in the evaluation of cirrhosis because it is the least expensive and does not pose a radiation exposure risk or involve intravenous contrast with the potential for nephrotoxicity as does computed tomography CT.

Nodularity, irregularity, increased echogenicity, and atrophy are ultrasonographic hallmarks of cirrhosis. In advanced disease, the gross liver appears small and multinodular, ascites may be detected, and Doppler flow can be significantly decreased in the portal circulation. The discovery of hepatic nodules via ultrasonography warrants further evaluation because benign and malignant nodules can have similar ultrasonographic appearances.

CT and magnetic resonance imaging MRI generally are poor at detecting morphologic changes associated with early cirrhosis, but they can accurately demonstrate nodularity and lobar atrophic and hypertrophic changes, as well as ascites and varices in advanced disease. Although MRI sometimes differentiates among regenerating or dysplastic nodules and hepatocellular carcinoma, it is best used as a follow-up study to determine whether lesions have changed in appearance and size.

Although used rarely, magnetic resonance angiography MRA can assess portal hypertensive changes including flow volume and direction, as well as portal vein thrombosis.

Referral for liver biopsy should be considered after a thorough, noninvasive serologic and radiographic evaluation has failed to confirm a diagnosis of cirrhosis; the benefit of biopsy outweighs the risk; and it is postulated that biopsy will have a favorable impact on the treatment of chronic liver disease.

The sensitivity and specificity for an accurate diagnosis of cirrhosis and its etiology range from 80 to percent, depending on the number and size of the histologic samples and on the sampling method.

Liver biopsy is performed via percutaneous, transjugular, laparoscopic, open operative, or ultrasonography- or CT-guided fine-needle approaches. Before the procedure, a CBC with platelets and prothrombin time measurement should be obtained. Patients should be advised to refrain from consumption of aspirin and nonsteroidal anti-inflammatory drugs for seven to 10 days before the biopsy to minimize the risk of bleeding.

Already a member or subscriber? Log in. Interested in AAFP membership? Learn more. Health Center. Address correspondence to Joel J. Heidelbaugh, M. Reprints are not available from the authors. National Center for Health Statistics. National Vital Statistics Report. Accessed May 2, , at: www. Heidelbaugh JJ, Sherbondy M. Cirrhosis and chronic liver failure. Part II: Complications and treatment. Am Fam Physician. Friedman S, Schiano T. Cirrhosis and its sequelae. In: Goldman L, Ausiello D, eds.

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Am J Gastroenterol. Diagnosis and monitoring of hepatic injury. Performance characteristics of laboratory tests. Clin Chem. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring. Non-invasive diagnosis of esophageal varices in chronic liver diseases. J Hepatol. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention.

Med Clin North Am. Adolesc Med Clin. Liver lesion characterization. Reston, Va. Simonovsky V. The diagnosis of cirrhosis by high resolution ultrasound of the liver surface. Br J Radiol. Lomas DJ. The liver. London, England: Churchill Livingstone, —8. PBC used to be a common indication for liver transplantation in adults. However, the proportion of patients with PBC who undergo liver transplantation has recently decreased, most probably because of the marked increase of transplantation for cirrhosis due to viral hepatitis, alcoholic liver disease and HCC.

The Mayo Risk Score, which calculates 2-year survival rate is useful in this regard. Recently, the MELD model for end-stage liver disease score has been found helpful to decide organ allocation of patients who are already on the waiting list. The score includes bilirubin, creatinine and INR international normalized ratio. The height of the serum bilirubin level alone is a very important factor when considering the appropriate timing of referral for liver transplantation assessment for patients with PBC.

The hallmark feature of recurrence is granulomatous bile duct destruction seen on liver biopsy. A plasma cell infiltrate also characterizes recurrent PBC and distinguishes it from other processes such as drug induced liver injury and acute or chronic rejection [ ].

Optimal immunosuppression needs to be provided to prevent recurrence of PBC. It is still controversial as to whether to use cyclosporine or tacrolimus [ , ]. Disease progression after recurrence is slow and retransplantation is rarely necessary. However, there is a report of graft failure due to recurrent disease [ ]. These features may present simultaneously but sometimes features of AIH develop acutely and change the overall pattern of the liver disease [ 46 ]. Corticosteroids are usually contraindicated in PBC because they enhance osteoporosis [ ], though their use is advocated by some authors for these patients.

However, a recent pilot study of a long-term outcome suggests that combination of UDCA and corticosteroids may be the best therapeutic option for a strictly defined PBC-AIH overlap syndrome [ ].

Very recent meta-analysis has shown that there are insufficient data to evaluate the efficacy of cholestyramine [ ]. This agent seems to bind bile that contains the unknown pruritogen of cholestasis in the gastrointestinal tract.

Usually it is helpful and effective when taken properly, i. It also has to be taken 4 hours apart from any other medications to avoid their binding. Patients need to appreciate that cholestyramine should be used for long-term prevention of pruritus. It may cause abdominal bloating and constipation.

Rifampin would be the second choice when cholestyramine is not effective, starting at mg twice daily. Usually, its benefit is appreciated in the first week to month of treatment and increasing the dose may help further in those patients who initially fail to respond.

Rifampin may be considered the first-line therapy for pruritus, but this has not been the case since its efficacy is not widely appreciated, and because of certain untoward side effects and contraindications.

Rifampin is an enzyme inducer, hence the potential to cause clinically relevant drug interactions should always be considered, i. Rifampin may cause hepatitis, hemolytic anemia and renal dysfunction, usually within the initial few weeks of therapy. Patients treated with rifampin need to be monitored closely in this regard. The precise mechanism of pruritus remains unclear. However, the efficacy of partial external biliary diversion, biliary drainage and plasmapheresis for intractable pruritus in patients with intrahepatic cholestasis suggest that pruritogen s such as circulating endogeneous opioids are present in both bile and blood [ — ], and increased levels are reported in patients with PBC [ ].

The efficacy of naloxone, an opioid antagonist, for the pruritus of chronic cholestasis supports this hypothesis and may be one of the alternatives when the patients have failed other treatments [ ]. Symptoms suggestive of narcotic withdrawal may develop in some patients, thus naloxone should be introduced at very low dose and be built up gradually, ideally by an experienced physician.

Attention to the chronic pain syndrome should be paid with long-term use [ ]. This suggests that serotonergic pathways are important in the perception of pruritus [ ]. Plasmapheresis should be considered when treatment of pruritus is urgently required, for example when the patient is suicidal due to severe and uncontrollable pruritus. Treatment with ultraviolet light may be beneficial, particularly when the symptom worsens during the winter. Fatigue is one of the most common presenting complaints in patients with PBC.

There is no known treatment for fatigue in PBC. However, complications such as hypothyroidism, anemia, depression or any other reasons for fatigue have to be carefully excluded rather than assuming PBC to be the cause, particularly as these complications may be treatable. Many drugs such as UDCA [ ], cyclosporine [ ], thalidomide [ ] and antioxidants [ ] have been investigated previously but failed to show any efficacy in controlling this debilitating symptom. Even though the cause of fatigue in PBC remains unclear, it may be related to dysfunction of either the corticotrophin-releasing hormone or serotonergic neurotransmitter systems [ ].

However, a randomized, controlled crossover trial of ondansetron a serotonin receptor antagonist did not confer clinically significant fatigue reduction [ ]. In a case series of 8 patients, methotrexate was shown to be efficacious for fatigue in PBC [ ].

More recent data suggest a possibility that fatigue is associated with excessive daytime somnolence and altered autonomic function [ , ]. Open label modafinil therapy a central nervous system stimulant used to treat narcolepsy was associated with improvement in excessive daytime somnolence and associated fatigue in PBC [ ]. Chronic cholestasis is associated with an increased risk of osteopenia and osteoporosis.

In the development of osteoporosis in PBC, there are two mechanisms that are commonly used to classify primary osteoporosis: "low-turnover" with normal resorption but reduced synthesis and slow mineralization of matrix and "high-turnover" with increased resorption due to reduced osteoblast function or increased activity of osteoclast [ , ]. Inherited predisposition to deficiency of vitamin D associated with particular genetic polymorphisms has been also reported [ ].

However, whether patients with PBC are at higher risk of developing osteoporosis than general population is controversial [ , ]. One study does suggest that osteoporosis is a feature of PBC, especially in those patients who are older, thinner and with more advanced liver disease [ ].

Recently, it has been confirmed in a population-based study that there is a modest increase in both the absolute fracture risks Additionally, bone fracture post-OLT occurs due to the combination of preexisting low bone mineral density and early post-OLT bone loss [ ]. Therefore, we should consider that all patients with PBC are at risk of osteoporosis, and prophylactic and therapeutic measures need to be undertaken.

Screening regularly for bone mineral density using non-invasive, dual energy X-ray absorptiometry DEXA scan , may identify bone changes prior to bone fractures.

Patients should be encouraged to take exercise on regular basis and be in the sunlight to activate vitamin D. The use of hormone replacement is controversial for postmenopausal patients since it may provide protection against bone loss, but may worsen cholestasis [ ].

Recently, alendronate has been demonstrated be more effective than bisphosphonate for the treatment of osteoporosis in PBC [ ]. A small pilot trial of vitamin K2 a fat-soluble vitamin that modulates bone metabolism similarly to vitamin D has shown the efficacy of vitamin K for treatment of osteoporosis in PBC patients [ ].

Nodular regenerative hyperplasia NRH is a condition characterized by hepatocytic nodules distributed throughout the liver without perinodular fibrosis and caused by occlusion of small portal veins in the portal tracts. However, nonselective beta-blockers are ineffective in preventing the development of varices in unselected patients with cirrhosis [ ]. There is a report showing earlier recurrence of esophageal varices, following endoscopic therapy, in patients with PBC compared with non-PBC patients [ ].

One large retrospective study has shown that there is an increased risk for development of hepatobiliary malignancies in PBC [ ]. Therefore, screening for HCC, for instance, ultrasound at 6 months interval, might be beneficial in these patients.

There are numerous reports on the natural history and prognosis of PBC in terms of clinical, biochemical, histological and treatment response. Most of the published data on survival in PBC indicate a poor prognosis but these data were obtained from patients who were diagnosed more than 2—3 decades ago and never received treatment [ 22 ].

It appears that, at present, the prognosis is much better than the previously reported, probably because patients are diagnosed at much earlier stage of the disease and treatments are instituted earlier.

The features of patients diagnosed with PBC nowadays are different from the days when this disease was first recognized and described.

Therefore, it is important that current patients take this into account when they read outdated reports on PBC! Although most patients are diagnosed and initiated on treatment in the asymptomatic phase, not all patients stay asymptomatic in long-term follow-up.

Another large cohort of patients with PBC has shown that the median survival or liver transplantation referral from diagnosis was 9. Patients who were asymptomatic at diagnosis did not live longer than their symptomatic counterparts but the median age of this cohort at baseline was over 60 years Several other reports, based on only a relatively small number of patient deaths during the follow-up period, suggest that the survival of patients asymptomatic at diagnosis falls significantly below than that of gender- and age-matched control groups [ — ].

However, these data are based on patients who had been diagnosed decades ago, before the introduction of UDCA. A substantial proportion of the asymptomatic patients at diagnosis ultimately became symptomatic. The only report of the natural history of histological changes in PBC without UDCA but with penicillamine or placebo has documented that the majority of patients will progress histologically within 2 years. UDCA appears to prevent the progression of the disease, particularly if started in early-stage disease.

A recent encouraging report from Spain has shown that in patients with an early-stage disease stage 1 or stage 2 , the biochemical response to UDCA after 1 year is associated with a similar survival to the matched control population [ ].

To date, no reliable way has been identified to predict which patients will remain asymptomatic. An older study of asymptomatic patients has suggested that the presence of hepatomegaly, advanced histological stage or the presence of associated autoimmune disorders is strongly predictive of the subsequent development of PBC-related symptoms pruritus, jaundice, ascites or variceal bleeding [ , ], while a more recent study has not been able to identify any prognostic variables that would distinguish patients who would become symptomatic from those who would remain asymptomatic [ ].

A recent report has suggested that the presence of anti gp one of the antibodies to nuclear antigens and especially when in high titer may predict those patients who will have a poor outcome [ ], but this has been disputed [ ].

As an environmental factor, smoking has been proven as a contributing risk factor for progression of the disease [ 76 ]. Classically, advanced age, elevated INR, jaundice, low serum albumin, edema, ascites and advanced histological stage are strongly correlated with median survival rates of less than 5 years from time of diagnosis in symptomatic patients. Serum total bilirubin is still one of the most reliable predictors for progression of the disease in PBC and it plays a cardinal role in current mathematical models for predicting survival, along with age, serum albumin, PT and severity of edema [ ].

The most common cause of death in patients with PBC remains liver failure. However, again, these numbers have been retrieved from studies in large tertiary referral centers before UDCA has been available, hence findings may not always reflect current experience.

Prospective cohort studies with observation for long periods with serial clinical, biochemical and histological data may provide data that helps to identify marker of disease progression in PBC.

The true significance of UDCA on disease course and natural history remains controversial. Lack of any effect in causing disease regression requires further studies on the pathogenesis of this disease to identify new therapeutic approaches. In this regard, the recent discovery of spontaneous animal models may allow us to better understand the pathogenesis of PBC in humans.

Further genetic research may provide a bridge to clinical research, perhaps indicating predictive markers of disease progression as well as facilitating the basis for developing novel approaches to therapy by throwing light on the pathogenesis of PBC.

Only these may determine why standard treatments for other autoimmune diseases are ineffective in PBC. It is hoped that a genetic explanation for the different patterns of disease presentation in PBC might be revealed and better targets for therapy still to be identified.

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