Fatty liver conceptual image, 3D illustration showing fatty liver silhouette made from micrograph of liver steatosis (Shutterstock)

The path to NASH: un­der­stand­ing the role of se­vere obe­si­ty in a com­plex, mul­ti-sys­tem dis­ease

Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to Amber Tong.

We of­ten think a per­son’s tran­si­tion from a healthy to a dis­eased state is bi­na­ry. But that’s of­ten not the case. In re­al­i­ty, the on­set of a dis­ease is not some­thing that oc­curs overnight, and the ma­jor­i­ty lie on a con­tin­u­um that is im­pact­ed by a mul­ti­tude of fac­tors. Some of these fac­tors are in a pa­tient’s con­trol. Oth­ers are not.

This is the case in non­al­co­holic fat­ty liv­er dis­ease (NAFLD) and non­al­co­holic steato­hep­ati­tis (NASH), two of the most com­plex dis­eases that “live” on this prover­bial con­tin­u­um. The clin­i­cal on­set of NAFLD — and ul­ti­mate­ly NASH — is a com­plex process that is close­ly re­lat­ed to obe­si­ty, in­sulin re­sis­tance and im­paired adi­pose tis­sue me­tab­o­lism.

For ex­am­ple, the preva­lence of NAFLD cor­re­lates with the in­creas­ing preva­lence of obe­si­ty. Sim­i­lar re­search has emerged in the NASH space: In a study an­a­lyz­ing pa­tients who sub­mit­ted to bariatric surgery, 70.4% of those pa­tients had NASH. The da­ta sug­gest that the world­wide preva­lence of obe­si­ty among NAFLD and NASH pa­tients is 51% and 81%, re­spec­tive­ly, and in pop­u­la­tions with obe­si­ty, NAFLD preva­lence varies from 60% to 95%.

While it is clear that a ma­jor con­trib­u­tor on this NASH con­tin­u­um is se­vere obe­si­ty, it pos­es its own set of chal­lenges. NASH re­searchers and drug de­vel­op­ers of­ten strug­gle to com­mu­ni­cate the role obe­si­ty plays in dis­ease on­set and pro­gres­sion in a way that is both kind and em­pa­thet­ic — and al­so sci­en­tif­i­cal­ly ac­cu­rate. That be­ing said, how­ev­er dif­fi­cult it is to achieve this del­i­cate bal­ance, it is cru­cial in or­der to ap­proach treat­ment holis­ti­cal­ly.

This is the chal­lenge we face as a com­pa­ny work­ing to ther­a­peu­ti­cal­ly ad­dress a dis­ease that is (in part) a re­sult of lifestyle choic­es. There’s an as­so­ci­at­ed stig­ma that gets placed on the in­di­vid­ual, and many strug­gle with feel­ing re­spon­si­ble for de­vel­op­ing a dis­ease that is so heav­i­ly linked to obe­si­ty and a low-ac­tiv­i­ty lifestyle.

The se­vere obe­si­ty that plagues most peo­ple with NASH comes with mo­bil­i­ty chal­lenges, and rou­tine, day-to-day tasks of­ten prove to be ma­jor hur­dles for peo­ple with this dis­ease. This fu­els a down­ward spi­ral of anx­i­ety, self-re­crim­i­na­tion and doubt, and in­di­vid­u­als will of­ten face poor self-es­teem fa­tigue and de­pres­sion as a re­sult. As a part of the biotech and health­care com­mu­ni­ties, our goal here is to judge, help, ed­u­cate and pro­vide mean­ing­ful treat­ment op­tions to the in­di­vid­u­als who need them most.

For ex­am­ple, this in­cludes ed­u­cat­ing peo­ple of the long-term risks as­so­ci­at­ed with years of an ex­cess of calo­ries con­sumed rel­a­tive to en­er­gy con­sump­tion. While we know that obe­si­ty can lead to a va­ri­ety of dis­eases and ail­ments, the ef­fects of a chron­ic ex­cess of calo­ries are not nec­es­sar­i­ly ob­vi­ous to every­one. The re­al­i­ty is that NASH, di­a­betes, car­dio­vas­cu­lar dis­ease (and more) are all con­nect­ed to a sur­feit of calo­ries over an ex­tend­ed pe­ri­od of time, and this ex­cess ul­ti­mate­ly dri­ves dis­ease pro­gres­sion.

What we need are open, com­pas­sion­ate con­ver­sa­tions that en­able in­di­vid­u­als to ex­plore where they are on this dis­ease con­tin­u­um and how to es­tab­lish bet­ter, health­i­er lifestyle choic­es. It’s not about sit­ting in judg­ment or “fat sham­ing.” It’s about ful­ly un­der­stand­ing how obe­si­ty and oth­er fac­tors can man­i­fest in dis­ease lat­er down the road. While most dis­ease pro­gres­sion lies on a con­tin­u­um, this is par­tic­u­lar­ly true for NASH.

In­di­vid­u­als should be helped to un­der­stand that obe­si­ty can be an avoid­able — and re­versible — pre­cur­sor to the dis­ease to en­sure that they re­ceive the best care pos­si­ble. Peo­ple ei­ther at risk for or liv­ing with NASH can im­prove their over­all health if they are will­ing to take a more ac­tive role in man­ag­ing their risk fac­tors. This can in­clude re­duc­ing calo­rie in­take and in­creas­ing ac­tiv­i­ty to re­duce weight, but oth­er vari­ables with re­spect to their health must al­so be con­sid­ered. For in­stance, in­di­vid­u­als at risk for NASH are fre­quent­ly pre­scribed a pletho­ra of oth­er med­ica­tions such as high blood pres­sure med­i­cines, di­a­betes drugs or statins, and anx­i­ety and de­pres­sion treat­ments for ad­di­tion­al dis­or­ders as­so­ci­at­ed with obe­si­ty.

Chang­ing eat­ing habits can im­pact drug ac­tiv­i­ty in the body and may cause un­fore­seen com­pli­ca­tions that should be tak­en in­to con­sid­er­a­tion to en­sure op­ti­mal care. That is why we can­not shy away from these con­ver­sa­tions, even as we prac­tice em­pa­thy and com­pas­sion.

NASH is a com­plex, mul­ti-sys­tem dis­ease, re­quir­ing pa­tient care and ther­a­peu­tics that ad­dress its mul­ti-fac­to­r­i­al na­ture. But treat­ing NASH ex­tends be­yond its clin­i­cal pro­file – it goes back to this no­tion of the con­tin­u­um. Clin­i­cians, re­searchers and drug de­vel­op­ers must ex­am­ine the en­tire per­son, con­fronting both the phys­i­cal and emo­tion­al tolls of NASH. The on­ly way to do this is through open and hon­est con­ver­sa­tions about the role of obe­si­ty in the dis­ease. On­ly then can we be­gin to ef­fec­tive­ly help the peo­ple who face this di­ag­no­sis.

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