The SHUNT-V Study for Varices

The purpose of this study is to validate the Disease Severity Index (DSI) from the HepQuant
SHUNT Liver Diagnostic Kit (Test) for likelihood of large esophageal varices. Our HALT-C
Training dataset demonstrated that the DSI 18.3 had sensitivity 95%, specificity 54%, PPV
19%, NPV >99%, negative likelihood ratio (NLR) 0.09, and positive likelihood ratio (PLR) 2.09
for large varices. To validate DSI 18.3 as a cutoff for large varices, we will enroll 420
subjects with chronic liver disease (CLD) of mixed etiologies from 15 to 25 US clinical
centers (CLD Validation dataset). The target prevalence of large varices is ≥20%. Each
subject will have been scheduled for an esophago-gastro-duodenoscopy (EGD) as part of their
standard of care for either variceal or non-variceal indications. Enrolled subjects will
undergo standard clinical assessment, laboratory tests, and the HepQuant SHUNT Test. The EGD
will be performed within 6 weeks following the HepQuant SHUNT Test. The relationship of DSI
to large varices will be analyzed by univariate and multivariate logistic regression
analyses, AUROC, and linear and nonlinear regression and correlation coefficients. Diagnostic
performance of the DSI cutoff will be defined in the CLD Validation dataset and validated for
likelihood of large esophageal varices. The validated DSI cutoff will identify subjects who
are either unlikely or likely to have large esophageal varices.

Inclusion Criteria:

- Ability to have a peripheral venous catheter for administration of the 13C cholate

- Ability to take the oral dose of d4-cholate

- Ability to hold morning doses of medications for the 90-minute duration of the
HepQuant SHUNT Test

- Meets the protocol defined criteria for CLD in addition to having the diagnoses of CLD
for >6 months

- Is scheduled, or in the process of being scheduled, for a standard of care EGD

Exclusion Criteria:

- Unable to give informed consent

- Unable to obtain venous access for administration of intravenous cholate

- Unable to absorb orally-administered cholate

- Known hypersensitivity to human serum albumin

- Known hypersensitivity to any of the components of the HepQuant SHUNT Liver Diagnostic
Kit

- Acute hepatitis or Acute Liver Failure

- Acute drug-induced liver disease (DILI)

- Noncirrhotic causes for portal hypertension and varices

- Ongoing active alcoholic hepatitis

- Child-Pugh class C defined by Child-Pugh score 10 or higher

- Dialysis

- Active infection or febrile illness within the last month

- Documented history of esophageal or gastric variceal hemorrhage

- Documented history of treatment of esophageal varices

- Documented history of endoscopic findings of large esophageal varices

- Hepatocellular carcinoma beyond Milan or UCSF criteria

- Thrombosis of main portal vein

- Liver transplant recipient

- Pregnancy

- Women who are breast-feeding

- Serious intercurrent medical or surgical illness, such as acute myocardial infarction,
acute cerebral hemorrhage, sepsis, or other immediate life-threatening illness