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5-14-2020

Cirrhosis for the PCP Cirrhosis for the PCP

Krys Foster, MD, MPH Thomas Jefferson University

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Cirrhosis for the PCP

Krys Foster, MD, MPHClinical Assistant Professor

Associate Residency Program DirectorSidney Kimmel Medical College @ TJU

Family Medicine Residency ProgramMay 14, 2020

12thCirrhosis and Chronic Liver Disease is the 12th leading cause of death in the

United States

Introduction:

● Cirrhosis is a heterogeneous disease of late stage progressive hepatic fibrosis

● It is often an indolent disease○ Often is discovered during a routine examination with laboratory or radiographic studies, or at

autopsy○ Most patients remain asymptomatic until “decompensation”○ Unfortunately, at that point, largely irreversible and poor prognosis

● Preventive strategies can maximize time before liver transplantation or death for those with early cirrhosis by avoiding further damage and mitigating comorbidity

Role as Primary Care Physicians...

● The incidence of liver cirrhosis is expected to increase in the near future

● PCPs play a key role in prevention, treatment, timely referrals to specialists and multidisciplinary team members (dieticians, psychologists, etc.), collaborative management, surveillance and home care of populations at risk!

Algorithm for the management of patients with (or with suspected) liver cirrhosis in General Practice

Objectives:

● Understand the morbidity and mortality associated with Cirrhosis in the United States

● Recognize etiologies and clinical presentation of cirrhosis● Identify decompensated cirrhosis and approaches to treatment and monitoring

Agenda:● Definition and Epidemiology● Etiologies● Clinical Presentation● Diagnosis and Evaluation/Classification● Management of Compensated Cirrhosis● Decompensated Cirrhosis & Complications

○ Portal Hypertension○ Varices○ Ascites○ SBP○ Hepatorenal Syndrome○ Hepatic Encephalopathy

● Secondary Prevention and Long Term Management● Conclusions

What is Cirrhosis?

Definition:

Hepatic parenchymal necrosis and an inflammatory response to the underlying cause

→ chronic hepatocellular injury

→ subsequent hepatic repair mechanisms lead to irreversible fibrosis and abnormal tissue architecture (nodular regeneration)

→ which ultimate results in impaired liver function

Impact of Liver Disease in the

US

Number of adults with diagnosed liver disease: 4.5 million

Percent of adults with diagnosed liver disease: 1.8%

Deaths per 100,000 population: 12.8

More common in adults ages 45-54

Epidemiology of Cirrhosis:

Prevalence: approx. 0.27%* in U.S. adults

Sex: ♂ > ♀ (2:1)

Responsible for approx. 1–2% of all deaths in the United States; most deaths occurring in the fifth to sixth decade of life

(likely an underestimate)*

Health Disparities related to Cirrhosis:

● Highest prevalence among non-Hispanic Blacks, Mexican Americans, those living below the poverty level, and those with less than a 12th grade education

● Additionally, there are disparities associated with referral to transplant centers and receipt of donor organs

● Public health efforts are needed to reduce this disease burden, particularly among racial/ethnic minorities and individuals at lower socioeconomic status

Scaglione S, Kliethermes S, Cao G, et al. The epidemiology of cirrhosis in the United States: a population-based study. J Clin Gastroenterol. 2015; 49(8): 690-696.

Costs to the Healthcare System:

● Cirrhosis and advanced liver disease cost the United States between $12 billion and $23 billion dollars in health care expenses annually

● Additionally, annual costs increase with decompensation; for instance:○ $2,400 for the treatment of diuretic-sensitive ascites○ $24,800 for the treatment of diuretic-refractory ascites○ $25,600 for the treatment of variceal hemorrhage○ $16,400 for the treatment of hepatic encephalopathy○ $44,200 for the treatment of hepatocellular carcinoma.

● In some sources, cited as “ranks eighth in economic cost among the major illnesses”

What Causes Cirrhosis?

Etiologies:

Wolf. Medscape. emedicine.medscape.com/article/185856-overview?src=emailthis#a4

How does cirrhosis present

clinically?

Name all of the main clinical features of cirrhosis of the liver.

Clinical Presentation

Common cutaneous manifestations of cirrhosis

Photo Credit: DermNet NZ

Early Findings:

Lab Findings:

● May be normal!● Incidentally noted elevated liver enzymes (AST, ALT, bilirubin)● Low albumin (<3.5g/dL)● Thrombocytopenia (<160K) ● Prolonged Prothrombin Time (PT)/Elevated INR

Other labs to order include: Alkaline Phosphatase, Gamma-glutamyl transferase, viral hepatitis serologies, ferritin, transferrin saturation, fasting lipid and a1c (if risk factors for NAFLD exist), consider studies for autoimmune hepatitis, ANA, Anti-SMAb, or others based on risk factors and clinical findings

Noninvasive Evaluation:

● Biomarkers (e.g. FibroSure) and non-proprietary, serum based calculators (e.g. AST to platelet ratio index [APRI], NAFLD fibrosis score, etc.)

● Ultrasonography○ Low cost, easily accessible○ Sensitive and specific for steatosis, but may miss fibrosis and cirrhosis (only 40-57% sensitive)

U/S: advanced cirrhotic liver appears to be nodular, irregular, and contracted with relatively enlarged caudate lobe (C) and lateral segment (L) of the left lobe. Fatty infiltration and fibrosis give a coarse echotexture of the liver parenchyma.

Transient Elastography:

Transient Elasticity

● Now more widely available; only takes 5 minutes!

● Rapidly replacing biopsy as preferred method for fibrosis staging

● U/S technique performed w/ specialized machine (Fibro-Scan) to determine liver stiffness by measuring velocity of low-frequency elastic shear waves propagating through the liver

● 81% sensitive and 88% specific for detecting liver fibrosis and cirrhosis

● Less accurate at distinguishing between stages of liver disease

● Less reliable in patients w/ obesity, ascites, excessive EtOH intake, extrahepatic cholestasis, acute hepatic inflammation

Liver Biopsy Indications:

● Concern for fibrosis remains after indeterminate or conflicting clinical, lab and imaging results

● Transient Elastography is not suitable● To clarify etiology of disease after inconclusive noninvasive evaluation

Still the reference standard in diagnosing cirrhosis, however a 20% error rate still occurs in fibrosis staging and use of noninvasive methods has become increasingly common in clinical practice

Classification:

Staging/Risk Stratification:

Child-Pugh score

Points 1 2 3

Serum albumin g/dL > 3.5 2.8–3.5 < 2.8

Serum bilirubin mg/dL < 2.0 2.0–3.0 > 3.0

INR < 1.7 1.7–2.3 > 2.3

Ascites None Mild Moderate

Hepatic encephalopathy None Minimal Advanced

Child-Pugh class A: 5–6 points; Child-Pugh class B: 7–9 points; Child-Pugh class C: 10–15 points

Management and Treating Complications...

Management and Prevention of Complications:

● primary goals are to prevent cirrhosis complications, liver decompensation, and death

● accomplished with rigorous prevention counseling (see next slide), monitoring, and management by primary care physicians, in consultation with subspecialists as needed

Routine Monitoring:

● Every 6 months to recalculate CP and MELD scores○ BMP○ LFT○ CBC○ PT/INR

● Refer for liver transplantation evaluation if:○ MELD ≥ 15○ Ascites○ Hepatic Encephalopathy○ Variceal Hemorrhage

Disease Progression:

Portal Hypertension:● PH is the initial and main consequence of cirrhosis and is responsible for the majority of its

complications.● Hepatic Venous Pressure Gradient (HVPG) is the gold standard for assessing severity of PH.

It’s an estimate of the pressure differential between the portal vein and IVC.

Varices:

● Portal hypertension predisposes patients with cirrhosis to develop esophageal varices

○ Gastroesophageal varices (GEV) are present in approximately 50% of patients with cirrhosis, but this depends on the clinical stage.

■ In patients with compensated cirrhosis, GEV are present in 30%-40%, whereas they can be present in up to 85% of patients with decompensated cirrhosis

○ Patients with varices have a one in three chance of developing a variceal bleed in the two years after diagnosis, with a 20% to 40% mortality rate per episode.

● Endoscopy is the preferred screening method for esophageal varices○ Many experts and guidelines recommend screening all patients with cirrhosis; however, newer

recommendations suggest targeted screening of patients with clinically significant portal hypertension.

○ Every 1-2 years if small varices found and every 2-3 years if no varices found

Variceal Hemorrhage

● Occurance rate of variceal hemorrhage varies depending on the severity of the liver disease, size of varices, and presence of variceal wall thinning (red wale marks)

○ ~10-15% per year

● Six-week mortality (the now-recognized primary endpoint to assess impact of therapies for acute hemorrhage) ranges between 15-25%!

Management of Varices and Variceal Hemorrhage● Primary Prophylaxis (see next slide)

● If bleeding, acute treatment goals include:○ hemodynamic resuscitation○ treatment of active bleeding○ prevention of rebleeding

■ Band ligation is the standard for the control of variceal bleeding. ■ If banding is difficult because of continued variceal bleeding, endoscopic sclerotherapy with

vasoconstrictors (e.g., octreotide) or a Sengstaken-Blakemore tube insertion (with adequate airway protection) may be used until TIPS or surgical treatment can be arranged.

● Recurrent or Treatment Resistant Hemorrhage:○ Pursue TIPS (transjugular intrahepatic portosystemic shunt) to lower portal pressure○ Can d/c beta blockers

TIPS

Procedure

● A needle catheter inserted via the internal jugular vein → passed along to hepatic vein → pierced through liver parenchyma to intrahepatic branch of the portal vein → expandable metal stent is placed → side-to-side portocaval shunt

● Assures blood drainage from the portal to the systemic system bypassing the liver, thus lowering portal pressure

Several contraindications...

Ascites:

● Abnormal accumulation of fluid in the peritoneal cavity○ Ddx includes conditions causing portal hypertension and/or hypoalbuminemia

● If ascites origin in unclear, can perform paracentesis and ascitic fluid assessment

Treating Ascites in Cirrhosis:

● Sodium Restriction!○ MAX 2000mg DAILY

● Spironolactone● Furosemide (if massive ascites)● Albumin

○ Administer if > 5L fluid removed during paracentesis

● Fluid Restriction?○ If serum sodium is less than 125 mEq per L

Need to monitor potassium and creatinine

If refractory or diuretics contraindicated → large volume paracentesis and consideration of TIPS

Spontaneous Bacterial Peritonitis:● Infx of peritoneal fluid. A common complication of uncontrolled ascites

○ Caused by translocation of gut bacteria or sepsis

● Presentation: signs of peritonitis, SIRS, worsening liver fx, hepatic encephalopathy, renal failure, shock, GI bleed…However, may be asymptomatic

● Diagnosed by PMN >250/mm³ or + Gram stain/culture on ascitic fluid● Historically, HIGH MORTALITY (related to renal failure); reduced to ~ 20% with early

diagnosis & treatment

Treatment for SBP

Start empiric tx (e.g. cefoxitime) and use ascitic culture to guide therapy, however pt’s may have culture-negative SBP

- May use ciprofloxacin unable to use cephalosporin- Consideration of resistance patterns (e.g. if pt on fluoroquinolone for ppx)

Most cases of SBP are due to gut bacteria such as E. coli and Klebsiella, though streptococcal and staphylococcal infections can also occur

Albumin should be administered from day 1-3 of treatment if Cr>1, BUN >30, tBili >4 to reduce risk of renal failure

d/c bb once SBP has developed (associated w/ increased mortality)

SBP - prophylactic antibiotics?Clinical Question:

Should antibiotic prophylaxis be used for hospitalized patients with cirrhosis and upper gastrointestinal bleeding?

Evidence-Based Answer:

Antibiotics should be used for prophylaxis in hospitalized patients with cirrhosis and upper gastrointestinal bleeding. (Strength of Recommendation: A, based on consistent results from two meta-analyses and a cohort study.)

Prophylaxis reduces all-cause mortality by 21%, as well as bacterial infections and rebleeding.

Hepatorenal Syndrome:

● Renal dysfunction secondary to reduction in renal blood flow in the setting of cirrhosis and portal hypertension

● Mainstay of treatment is vasopressor therapy with albumin○ Attempt to reverse splanchnic vasodilation and improve renal blood flow○ Primarily terlipressin and noradrenalin

● Limited role for Renal replacement therapy or TIPS● Leads to death in the absence of liver transplantation :(

RI = resistive indices

Hepatic Encephalopathy:

● Brain dysfunction caused by liver insufficiency and failure to detoxify NH3● Wide spectrum of neurologic/ psychiatric abnormalities from mild cognitive loss to

confusion to coma○ Onset may be gradual or sudden○ May include movement problems, changes in mood, confusion, disordered sleep, or changes in

personality

● Pitfalls: High blood ammonia levels alone add no diagnostic, staging, or prognostic value . . .

Treatment options for Hepatic Encephalopathy

Other Complications of Cirrhosis

● bone diseases, such as Osteoporosis● Biliary disease and Gallstones● Malabsorption and Malnutrition● Bruising and Bleeding easily ● Sensitivity to Medicines (limited drug metabolism)● Insulin resistance and Type 2 diabetes

Secondary Prevention

Preventing Superimposed Liver Insults:

● Avoidance of hepatotoxins● Medication Adjustments● Vaccinations

Weight Reduction/Obesity Management:

Careful dietary counseling and encouragement of weight loss is vital to reducing mortality

Dietary Counseling

Surveillance

Assess Cirrhosis Patients for Hepatocellular Carcinoma:

- AASLD recommends U/S + α‐fetoprotein every 6-12 months- Data is currently lacking**

Monitoring for patients with Varices:

- Upper Endoscopy every 1-2 years- Newer guidelines suggest targeted screening for esophageal varices in patients

with clinically significant portal hypertension rather than screening all patients with cirrhosis

Liver Transplantation

● Organ transplantation has become standard of care for patients with end-stage liver, kidney, lung and heart disease

● Liver is the second most commonly transplanted organ

● 90% 1 yr and 80% 5 yr survival

Conclusions:

● Liver cirrhosis has an increasing prevalence worldwide, which matches the increase in viral hepatitis infection and metabolic steatohepatitis

● Liver transplantation is standard of care for end stage liver disease, however access is limited

● PCP’s role in prevention, surveillance, and secondary prevention to reduce decompensation are vital to reducing morbidity and mortality from chronic liver disease

References:Angeli, Paolo, et al. “EASL Clinical Practice Guidelines for the Management of Patients with Decompensated Cirrhosis.” Journal of Hepatology, vol. 69, no. 2, 2018, pp. 406–460., doi:10.1016/j.jhep.2018.03.024.

Bass, Nathan. “Rifaximin Treatment in Hepatic Encephalopathy.” New England Journal of Medicine, vol. 362, no. 25, 2010, pp. 2423–2425., doi:10.1056/nejmc1004719.

“Cirrhosis.” AMBOSS, www.amboss.com/us/knowledge/Cirrhosis.

Fedor, Brad. Cirrhosis. www.hospitalmedicine.org/globalassets/professional-development/clinical-quick-talks-pdfs/cqt-table-images/cirrhosis-by-brad-fedor.pdf.

Garcia‐Tsao, Guadalupe, et al. “Portal Hypertensive Bleeding in Cirrhosis: Risk Stratification, Diagnosis, and Management: 2016 Practice Guidance by the American Association for the Study of Liver Diseases.” Hepatology, vol. 65, no. 1, 2016, pp. 310–335., doi:10.1002/hep.28906.

Ge, Phillip S., and Bruce A. Runyon. “Treatment of Patients with Cirrhosis.” New England Journal of Medicine, vol. 375, no. 8, 2016, pp. 767–777., doi:10.1056/nejmra1504367.

References (continued):Heidelbaugh, JJ, and Bruderly M. “Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation.” American Family Physician, vol. 74, no. 5, Sept 2006, pp. 756-762.

Heidelbaugh, JJ, and Bruderly M. “Cirrhosis and chronic liver failure: part II. Complications and Treatment.” American Family Physician, vol. 74, no. 5, Sept 2006, pp. 767-776.

Lee, Edward Wolfgang, et al. “Management Options for Gastric Variceal Hemorrhage.” JAMA Surgery, vol. 154, no. 6, 2019, p. 540., doi:10.1001/jamasurg.2019.0407.

Schiavo, Luigi, et al. “Nutritional Issues in Patients with Obesity and Cirrhosis.” World Journal of Gastroenterology, vol. 24, no. 30, 2018, pp. 3330–3346., doi:10.3748/wjg.v24.i30.3330.

Smith, Andrew, et al. “Cirrhosis: Diagnosis and Management.” American Family Physician, vol. 100, no. 12, 15 Dec. 2019, pp. 759–770.

Starr, S Paul, and Raines, Daniel. “Cirrhosis: Diagnosis, Management, and Prevention.” American Family Physician, vol. 84, no. 12, Dec 2011, pp. 1353-1359.

Uptodate: "Cirrhosis in adults: Overview of complications, general management, and prognosis" https://www.uptodate.com/contents/cirrhosis-in-adults-overview-of-complications-general-management-and-prognosis?search=cirrhosis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2

Thank You!